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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cell. Infect. Microbiol.</journal-id>
<journal-title>Frontiers in Cellular and Infection Microbiology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cell. Infect. Microbiol.</abbrev-journal-title>
<issn pub-type="epub">2235-2988</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcimb.2022.991657</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cellular and Infection Microbiology</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>
<italic>Proteus mirabilis</italic> and <italic>Klebsiella pneumoniae</italic> as pathogens capable of causing co-infections and exhibiting similarities in their virulence factors</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Palusiak</surname>
<given-names>Agata</given-names>
</name>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1320402"/>
</contrib>
</contrib-group>
<aff id="aff1">
<institution>Laboratory of General Microbiology, Department of Biology of Bacteria, Institute of Microbiology, Biotechnology and Immunology, University of &#x141;&#xf3;d&#x17a;</institution>, <addr-line>&#x141;&#xf3;d&#x17a;</addr-line>, <country>Poland</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Charles Martin Dozois, Universit&#xe9; du Qu&#xe9;bec, Canada</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Jorge Alberto Giron, University of Puebla, Mexico; Mark T. Anderson, Michigan Medicine, University of Michigan, United States</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Agata Palusiak, <email xlink:href="mailto:agata.palusiak@biol.uni.lodz.pl">agata.palusiak@biol.uni.lodz.pl</email>
</p>
</fn>
<fn fn-type="other" id="fn002">
<p>This article was submitted to Molecular Bacterial Pathogenesis, a section of the journal Frontiers in Cellular and Infection Microbiology</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>20</day>
<month>10</month>
<year>2022</year>
</pub-date>
<pub-date pub-type="collection">
<year>2022</year>
</pub-date>
<volume>12</volume>
<elocation-id>991657</elocation-id>
<history>
<date date-type="received">
<day>11</day>
<month>07</month>
<year>2022</year>
</date>
<date date-type="accepted">
<day>03</day>
<month>10</month>
<year>2022</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2022 Palusiak</copyright-statement>
<copyright-year>2022</copyright-year>
<copyright-holder>Palusiak</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>The genera <italic>Klebsiella</italic> and <italic>Proteus</italic> were independently described in 1885. These Gram-negative rods colonize the human intestinal tract regarded as the main reservoir of these opportunistic pathogens. In favorable conditions they cause infections, often hospital-acquired ones. The activity of <italic>K. pneumoniae</italic> and <italic>P. mirabilis</italic>, the leading pathogens within each genus, results in infections of the urinary (UTIs) and respiratory tracts, wounds, bacteremia, affecting mainly immunocompromised patients. <italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> cause polymicrobial UTIs, which are often persistent due to the catheter biofilm formation or increasing resistance of the bacteria to antibiotics. In this situation a need arises to find the antigens with features common to both species. Among many virulence factors produced by both pathogens urease shows some structural similarities but the biggest similarities have been observed in lipids A and the core regions of lipopolysaccharides (LPSs). Both species produce capsular polysaccharides (CPSs) but only in <italic>K. pneumoniae</italic> these antigens play a crucial role in the serological classification scheme, which in <italic>Proteus</italic> spp. is based on the structural and serological diversity of LPS O-polysaccharides (OPSs). Structural and serological similarities observed for <italic>Klebsiella</italic> spp. and <italic>Proteus</italic> spp. polysaccharides are important in the search for the cross-reacting vaccine antigens.</p>
</abstract>
<kwd-group>
<kwd>core oligosaccharide</kwd>
<kwd>
<italic>Klebsiella pneumoniae</italic>
</kwd>
<kwd>lipopolysaccharide</kwd>
<kwd>
<italic>Proteus mirabilis</italic>
</kwd>
<kwd>virulence factors</kwd>
</kwd-group>
<counts>
<fig-count count="3"/>
<table-count count="2"/>
<equation-count count="0"/>
<ref-count count="136"/>
<page-count count="18"/>
<word-count count="9572"/>
</counts>
</article-meta>
</front>
<body>
<sec id="s1">
<title>1 Introduction</title>
<p>Both <italic>Klebsiella</italic> spp. and <italic>Proteus</italic> spp. are Gram-negative rods belonging to the <italic>Enterobacterales</italic> ord. nov (<xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B1">Adeolu et&#xa0;al., 2016</xref>). In contrast to <italic>Klebsiella</italic> spp., <italic>Proteus</italic> spp. rods are motile (peritrichously flagellated) and capable of swarming. Swarming growth is triggered by a contact of short rod shaped swimmer cells (normally appearing in liquid medium) with 1.5% agar medium when the swimmer cells differentiate into elongated, hyperflagellated, multinucleated swarm cells. Swarmer cells move together across a plate till the population is reduced in its density and the consolidation process starts. In consolidation, which is regarded as a resting stage, swarmer cells re-differentiate into swimmer cells. The whole process is repeated till the characteristic bull&#x2019;s-eye pattern appears on agar media (<xref ref-type="bibr" rid="B5">Armbruster and Mobley, 2012</xref>; <xref ref-type="bibr" rid="B108">R&#xf3;&#x17c;alski et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B110">Schaffer and Pearson, 2015</xref>). By contrast, a feature, which distinguishes encapsulated <italic>Klebsiella</italic> spp. from <italic>Proteus</italic> spp. is a mucoid character of its colonies on agar media (<xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>). Both genera were described and named in the same year, 1885, <italic>Klebsiella</italic> &#x2013; by Trevisan to honor the German microbiologist Edwin Klebs, and <italic>Proteus</italic> &#x2013; by Hauser with reference to the Greek deity and the swarming nature of the bacteria (<xref ref-type="bibr" rid="B87">O&#x2019;Hara et&#xa0;al., 2000</xref>; <xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>).</p>
<p>The taxonomy of each genus has been modified, although the taxonomic history of <italic>Klebsiella</italic> spp. aroused some controversial opinions concerning: the exclusion of <italic>K. planticola</italic> from the genus <italic>Klebsiella</italic> and transferring this species, together with <italic>K. terrigena</italic> and <italic>K. ornithinolytica</italic>, to the new genus <italic>Raoultella</italic> on the basis of the <italic>rpoB</italic> phylogenies (<xref ref-type="bibr" rid="B101">Podschun and Ullmann, 1998</xref>; <xref ref-type="bibr" rid="B24">Drancourt et&#xa0;al., 2001</xref>; <xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>). Currently, in the genus <italic>Klebsiella</italic> two major species are well known as causing infections in humans: <italic>Klebsiella pneumoniae</italic> with three subspecies &#x2013; <italic>pneumoniae</italic>, <italic>ozaenae</italic> and <italic>rhinoscleromatis</italic> as well as <italic>K. oxytoca</italic>. Both species have been found to be genetically heterogeneous and comprise phylogenetic groups. <italic>K. pneumonia</italic> is subdivided into seven phylogroups (Kp1-Kp7) and <italic>K. oxytoca</italic> &#x2013; into six phylogroups (Ko1-Ko4, Ko6, Ko8) corresponding to the following taxa: Kp1 &#x2013; <italic>K. pneumoniae</italic>, Kp2 &#x2013; <italic>K</italic>. <italic>quasipneumoniae</italic> subsp. <italic>quasipneumoniae</italic>, Kp3 &#x2013; <italic>K</italic>. <italic>variicola</italic> subsp. <italic>variicola</italic>, Kp4 &#x2013; <italic>K. quasipneumoniae</italic> subsp. <italic>similipneumoniae</italic>, Kp5 &#x2013; <italic>K</italic>. <italic>variicola</italic> subsp. <italic>tropicalensis</italic>, Kp6 &#x2013; <italic>K</italic>. <italic>quasivariicola</italic>, Kp7 &#x2013; <italic>K</italic>. <italic>africanensis</italic>; Ko1 &#x2013; <italic>K</italic>. <italic>michiganensis</italic>, Ko2 &#x2013; <italic>K</italic>. <italic>oxytoca</italic>, Ko3 &#x2013; <italic>K</italic>. <italic>spallanzanii</italic>, Ko4 &#x2013; <italic>K</italic>. <italic>pasteurii</italic>, Ko6 &#x2013; <italic>K</italic>. <italic>grimontii</italic> and Ko8 &#x2013; <italic>K</italic>. <italic>hauxiensis</italic> (<xref ref-type="bibr" rid="B39">G&#xf3;mez et&#xa0;al., 2021</xref>).</p>
<p>Phylogenetic analysis resulted in placing <italic>Proteus</italic> within a new <italic>Morganellaceae</italic> family (<xref ref-type="bibr" rid="B1">Adeolu et al., 2016</xref>). The genus <italic>Proteus</italic> includes three unnamed <italic>Proteus</italic> genomospecies 4, 5 and 6, ten named species: <italic>P. mirabilis</italic>, <italic>P. vulgaris</italic>, <italic>P. penneri</italic>, <italic>P. hauseri</italic> and six newly formed species, <italic>P. cibarius</italic>, <italic>P. terrae</italic>, <italic>P. cibi</italic>, <italic>P. columbae</italic>, <italic>P. alimentorum</italic> and <italic>P. faecis</italic> (<xref ref-type="bibr" rid="B21">Dai et&#xa0;al., 2019</xref>).</p>
</sec>
<sec id="s2">
<title>2 <italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> as etiologic agents of infections in humans</title>
<p>The representatives of both genera colonize the lower human intestinal tract, but <italic>Klebsiella</italic> spp. were more prevalent (<xref ref-type="bibr" rid="B25">Drzewiecka, 2016</xref>). <italic>Klebsiella</italic> spp. also colonize the nasopharynx (<xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B91">Paczosa and Mecsas, 2016</xref>). The human digestive tract is regarded as a reservoir of both opportunistic pathogens leading to autoinfection or person-to-person transmitted nosocomial infections (<xref ref-type="bibr" rid="B25">Drzewiecka, 2016</xref>; <xref ref-type="bibr" rid="B91">Paczosa and Mecsas, 2016</xref>; <xref ref-type="bibr" rid="B39">G&#xf3;mez et&#xa0;al., 2021</xref>). <italic>Klebsiella</italic> spp. accounted for 3-9.9% of all nosocomial bacterial infections and <italic>Proteus</italic> spp. (<italic>P. mirabilis</italic>) &#x2013; for 3-5% of such infections depending on the survey (<xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B79">Magill et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B81">Martin and Bachman, 2018</xref>). Among <italic>Proteus</italic> species, <italic>P. mirabilis</italic> is the most important etiological factor of infections (80-90% of all <italic>Proteus</italic> infections), which has also been confirmed by the studies performed on 617 <italic>Proteus</italic> spp. strains collected in &#x141;&#xf3;d&#x17a; (2006&#x2013;2011) from different clinical sources (86.9% of isolation frequency) (<xref ref-type="bibr" rid="B28">Drzewiecka et&#xa0;al., 2021</xref>). Among <italic>Klebsiella</italic> species, <italic>K. pneumoniae</italic> is responsible for 75-86% of <italic>Klebsiella</italic> species infections (<xref ref-type="bibr" rid="B131">Watanakunakorn, 1991</xref>; <xref ref-type="bibr" rid="B41">Hansen et&#xa0;al., 2004</xref>). <italic>K</italic>. <italic>pneumoniae</italic> and <italic>P. mirabilis</italic> nosocomial infections include infections of the urinary tract (UTIs), wounds and bacteremia, which affect mainly immunocompromised patients especially in neonatal intensive-care units (<italic>K. pneumoniae</italic>) (<xref ref-type="bibr" rid="B34">Endimiani et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B108">R&#xf3;&#x17c;alski et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B81">Martin and Bachman, 2018</xref>; <xref ref-type="bibr" rid="B39">G&#xf3;mez et&#xa0;al., 2021</xref>). On the contrary, a hypervirulent variant of <italic>K. pneumoniae</italic> (hvKP) is capable of causing serious infections <italic>e.g.</italic> endophthalmitis and meningitis, which can be metastatically spread to distant sites in non-immunocompromised ambulatory younger healthy hosts (<xref ref-type="bibr" rid="B114">Shon et&#xa0;al., 2013</xref>).</p>
<p>Both <italic>K. pneumoniae</italic> and <italic>P. mirabilis</italic> strains are etiologic agents of bloodstream infections (BSIs), where <italic>K. pneumoniae</italic> isolates which are regarded as one of predominant species among <italic>Enterobacterales</italic> bacilli (4.4-36% depending on the surveillance) cause BSI (<xref ref-type="bibr" rid="B34">Endimiani et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B84">Musicha et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B71">Leal et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B55">Kallel et&#xa0;al., 2020</xref>). <italic>K. pneumoniae</italic> BSIs often associated with the MDR phenotype. In contrast to the well-proven contribution of <italic>K. pneumoniae</italic> to BSIs, <italic>P. mirabilis</italic> are isolated less often (0.3-2.9%) from blood samples (<xref ref-type="bibr" rid="B84">Musicha et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B71">Leal et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B55">Kallel et&#xa0;al., 2020</xref>). An occurrence frequency of BSIs may also depend on a world region <italic>e</italic>.<italic>g</italic>. no <italic>P. mirabilis</italic> strains out of 536 collected in &#x141;&#xf3;d&#x17a; (Poland) came from blood (<xref ref-type="bibr" rid="B28">Drzewiecka et&#xa0;al., 2021</xref>). <italic>P. mirabilis</italic> BSIs mostly originate from complicated UTIs in patients with community-acquired infections (<xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2012</xref>). Two cases of <italic>P. mirabilis</italic> bacteraemia originating from infected aneurysm have also been noted (<xref ref-type="bibr" rid="B85">Nagiah and Badbess, 2018</xref>). <italic>Klebsiella</italic> bacteraemia (both primary and secondary) arise from a primary infection in the bladder or lungs (<xref ref-type="bibr" rid="B91">Paczosa and Mecsas, 2016</xref>).</p>
<p>Although <italic>K. pneumoniae</italic> is a primary cause of hospital-acquired pneumonia -11.8% of HAPs- (often severe with characteristic brick-red sputum and often leading to local necrosis in lungs), hospital-acquired pneumonia caused by <italic>P. mirabilis</italic> has also been reported (usually mild or moderate with a good efficacy rate, often affecting elderly patients with underlying diseases) (<xref ref-type="bibr" rid="B134">Wu and Li, 2015</xref>; <xref ref-type="bibr" rid="B109">S&#x119;kowska and Gospodarek, 2007</xref>; <xref ref-type="bibr" rid="B88">Okimoto et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B79">Magill et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B91">Paczosa and Mecsas, 2016</xref>). Both species have been relatively rarely found among pathogens causing community-acquired pneumonia (CAP) in Europe (<xref ref-type="bibr" rid="B61">Ko et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B88">Okimoto et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B75">Lin et&#xa0;al., 2010</xref>). However, <italic>K. pneumonia</italic> has been found to be the underlying agent of CAPs in Asia and Africa, which is related to the increased prevalence of hvKP in these regions (<xref ref-type="bibr" rid="B61">Ko et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B91">Paczosa and Mecsas, 2016</xref>).</p>
<p>
<italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> species have also been reported to play a role in diarrheal disease (<xref ref-type="bibr" rid="B77">Lu. et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B136">Zhang et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B40">Gong et&#xa0;al., 2019</xref>). In China the detection rate of <italic>K. pneumoniae</italic> in faeces of persons with diarrhea was found to range from 0.5% among outpatients to 7.8% among hospital patients. In the majority of cases hypermucoviscosity phenotypes of <italic>K. pneumoniae</italic> were detected (<xref ref-type="bibr" rid="B77">Lu. et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B136">Zhang et&#xa0;al., 2018</xref>). Recently a novel diarrheagenic <italic>P. mirabilis</italic> strain (C02011) has been isolated in feces specimens in a food poisoning case in China. That strain was found to be a stronger gastrointenstinal pathogen than <italic>P. mirabilis</italic> B02005 isolated from healthy people. Moreover, the type IV secretion system (T4SS), also found in <italic>K. pneumoniae</italic>, was suggested to be crucial in the pathogenesis of diarrheal <italic>P. mirabilis</italic> (<xref ref-type="bibr" rid="B40">Gong et&#xa0;al., 2019</xref>). It is worth noting that both pathogens cause diarrhea in humans less often than other infections <italic>e</italic>.<italic>g</italic>. UTIs (<xref ref-type="bibr" rid="B87">O&#x2019;Hara et&#xa0;al., 2000</xref>; <xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>).</p>
<p>
<italic>K. pneumoniae</italic> and <italic>P. mirabilis</italic> cause community- and hospital-acquired urinary tract infections (UTIs) (<xref ref-type="bibr" rid="B109">S&#x119;kowska and Gospodarek, 2007</xref>; <xref ref-type="bibr" rid="B20">Cuevas et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2012</xref>). <italic>K. pneumonia</italic> is a causative agent of 2 to 6% of nosocomial UTIs and 4.3 to 7% of community-acquired ones (<xref ref-type="bibr" rid="B69">Laupland et&#xa0;al., 2007</xref>; <xref ref-type="bibr" rid="B74">Linhares et&#xa0;al., 2013</xref>; <xref ref-type="bibr" rid="B91">Paczosa and Mecsas, 2016</xref>). Depending on the studies and the world region, <italic>P. mirabilis</italic> placed third (behind <italic>E. coli</italic> and <italic>Klebsiella</italic> spp.) or fourth as a causative agent of UTIs (<xref ref-type="bibr" rid="B17">Coban et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B117">Tajbakhsh et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B27">Drzewiecka and Lewandowska, 2016</xref>). The isolation frequency from UTIs cases within one study was at a similar level for both pathogens and the numbers were much lower than those for <italic>E. coli</italic> (<italic>E. coli</italic> 81.8%, <italic>K. pneumoniae</italic> 7.9%, <italic>P. mirabilis</italic> 5.2% - Spain, 2008-2009) (<xref ref-type="bibr" rid="B20">Cuevas et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B27">Drzewiecka and Lewandowska, 2016</xref>). Both <italic>K. pneumoniae</italic> and <italic>P. mirabilis</italic> cause complicated UTIs in individuals with structurally abnormal urinary tracts, those undergoing long-term catheterization or patients with type 2 diabetes mellitus, but the latter species dominates as a causative agent of complicated UTIs (<xref ref-type="bibr" rid="B22">Dhingra, 2008</xref>; <xref ref-type="bibr" rid="B27">Drzewiecka and Lewandowska, 2016</xref>).</p>
<p>
<italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> are a common cause of catheter-associated UTIs (CAUTIs) (<xref ref-type="bibr" rid="B112">Schroll et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B6">Armbruster et&#xa0;al., 2018</xref>). <italic>P. mirabilis</italic> CAUTIs often affect long-term catheterized patients (28 days or longer) where they lead to pyelonephritis, urolithiasis, prostatitis, stone and biofilm formation (<xref ref-type="bibr" rid="B37">Fox-Moon and Shirtliff, 2015</xref>; <xref ref-type="bibr" rid="B5">Armbruster and Mobley, 2012</xref>; <xref ref-type="bibr" rid="B6">Armbruster et&#xa0;al., 2018</xref>). In catheter biofilms <italic>P. mirabilis</italic> was found together with <italic>K. pneumoniae</italic>, representatives of both species were isolated more often from mixed-species biofilms (34.2% and 23.7%, respectively) than from single-species ones (20.0% and 3.3%, respectively), however this correlation can be better noticed for <italic>K. pneumoniae</italic> isolates (<xref ref-type="bibr" rid="B78">Macleod and Stickler, 2007</xref>). After the infection of 72 h <italic>K. pneumoniae</italic> biofilm by <italic>P. mirabilis</italic>, <italic>K. pneumoniae</italic> showed temporary antagonism against <italic>P. mirabilis</italic> and extended twice its mean time to catheter blockage compared to the control (<xref ref-type="bibr" rid="B78">Macleod and Stickler, 2007</xref>). Conversely, co-inoculation of <italic>K</italic>. <italic>p</italic>.-<italic>P</italic>. <italic>m</italic>. did not impact the <italic>P. mirabilis</italic> ability to attach to the siliconized surface but impaired the ability of <italic>K. pneumonia</italic> to bind to that surface (<xref ref-type="bibr" rid="B38">Galv&#xe1;n et&#xa0;al., 2016</xref>). The persistence of UTIs caused by both pathogens may be connected with their increasing resistance to antibiotics, especially to nitrofurantoin commonly used in UTIs treatment. Moreover, the persistence of <italic>P. mirabilis</italic>-associated UTIs may result from urolithiasis that may lead to the catheters and urinary tract obstruction (<xref ref-type="bibr" rid="B48">Jacobsen et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B20">Cuevas et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B27">Drzewiecka and Lewandowska, 2016</xref>). 65% of specimens from patients with long-term catheterization contained <italic>P. mirabilis</italic>, which was associated with the catheter obstruction (<xref ref-type="bibr" rid="B83">Mobley and Warren, 1987</xref>). The dual-species associations of <italic>K</italic>. <italic>p</italic>. with <italic>P</italic>. <italic>m</italic>. were found to account for 7% of the 97% polymicrobial cases of CAUTIs in a two-year survey (<xref ref-type="bibr" rid="B38">Galv&#xe1;n et&#xa0;al., 2016</xref>).</p>
<p>Apart from polymicrobial UTIs, other infections may also be caused by the representatives of both species <italic>e.g. P. mirabilis</italic> and <italic>K. pneumoniae</italic> were isolated from the abdominal wound of a man with the carcinoma of the colon (<xref ref-type="bibr" rid="B63">Krajden et&#xa0;al., 1987</xref>). What is interesting, both species have been implicated in chronic inflammatory arthritis: <italic>K. pneumoniae</italic> in ankylosing spondylitis (AS) and <italic>P. mirabilis</italic> in rheumatoid arthritis (RA). In both cases the role of <italic>K. pneumoniae</italic> and <italic>P. mirabilis</italic> in the development of AS or AR, respectively, was associated with the molecular similarity between amino acid sequences of bacterial antigens and appropriate human self-antigens (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>) (<xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B105">Rashid and Ebringer, 2007a</xref>; <xref ref-type="bibr" rid="B106">Rashid and Ebringer, 2007b</xref>; <xref ref-type="bibr" rid="B108">R&#xf3;&#x17c;alski et&#xa0;al., 2012</xref>). The etiopathogenic role of <italic>K. pneumoniae</italic> in the AS development is connected with a molecular homology between: 1) &#x2018;QTDRED&#x2019; amino acid sequences present in both <italic>K. pneumoniae</italic> nitrogenase reductase enzyme and HLA-B27, 2) between &#x2018;DRDE&#x2019; amino acid sequences found in PulD secretion proteins of <italic>K. pneumoniae</italic> pullulanase enzyme and the &#x2018;DRED&#x2019; sequence in HLA-B27, 3) between repeating sequences occurring in PulA of <italic>Klebsiella</italic> spp. pullulanase and types I, III and IV collagens (<xref ref-type="bibr" rid="B113">Schwimmbeck et&#xa0;al., 1987</xref>; <xref ref-type="bibr" rid="B36">Fielder et&#xa0;al., 1995</xref>). On the other hand, the potential role of <italic>P. mirabilis</italic> in the etiopathogenesis of RA is associated with molecular similarity between: 1) the &#x2018;ESRRAL&#x2019; amino acid sequences found in <italic>P. mirabilis</italic> hemolysins and the &#x2018;EQ/KRRAA, motif observed in RA-associated HLA-DR molecules, 2) between the &#x2018;LRREI&#x2019; sequences in <italic>Proteus</italic> urease and the &#x2018;IRRET&#x2019; motif present in type XI collagen. In both cases high titers of antibodies against <italic>K. pneumoniae</italic> or <italic>P. mirabilis</italic> were detected in the sera of the patients with active AS or RA, respectively (<xref ref-type="bibr" rid="B31">Ebringer et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B133">Wilson et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B32">Ebringer et&#xa0;al., 2003</xref>; <xref ref-type="bibr" rid="B33">Ebringer et&#xa0;al., 2006</xref>). As a consequence of the mimicry phenomenon, bacterial antigen-specific antibodies, acting as autoantibodies, recognize also human self-antigens, which results in the damage to hyaline cartilage (<xref ref-type="bibr" rid="B133">Wilson et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B60">Konieczna et&#xa0;al., 2012</xref>). Different body sites are regarded as the isolation sources of both pathogens in RA or AS infections &#x2013; the upper urinary tract of RA patients (<italic>P. mirabilis</italic>) and the colon of AS patients (<italic>K. pneumoniae</italic>) (<xref ref-type="bibr" rid="B105">Rashid and Ebringer, 2007a</xref>; <xref ref-type="bibr" rid="B106">Rashid and Ebringer, 2007b</xref>).</p>
<table-wrap id="T1" position="float">
<label>Table&#xa0;1</label>
<caption>
<p>Molecular similarities between human self-antigens and appropriate <italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> enzymes (<xref ref-type="bibr" rid="B113">Schwimmbeck et&#xa0;al., 1987</xref>; <xref ref-type="bibr" rid="B31">Ebringer et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B36">Fielder et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B133">Wilson et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B32">Ebringer et&#xa0;al., 2003</xref>; <xref ref-type="bibr" rid="B33">Ebringer et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B105">Rashid and Ebringer, 2007a</xref>; <xref ref-type="bibr" rid="B106">Rashid and Ebringer, 2007b</xref>; <xref ref-type="bibr" rid="B60">Konieczna et&#xa0;al., 2012</xref>).</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" colspan="2" align="left">
<italic>K. pneumoniae</italic>
</th>
<th valign="top" colspan="2" align="center">Human self-antigens</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">Nitrogenase reductase</td>
<td valign="top" align="left">
<bold>Glu-Thr-Asp-Arg-Glu-Asp</bold>
</td>
<td valign="top" align="left">HLA-B27</td>
<td valign="top" align="left">
<bold>Glu-Thr-Asp-Arg-Glu-Asp</bold>
</td>
</tr>
<tr>
<td valign="top" align="left">Pullulanases:</td>
<td valign="top" align="left"/>
<td valign="top" align="left"/>
<td valign="top" align="left"/>
</tr>
<tr>
<td valign="top" align="left">Pul-D</td>
<td valign="top" align="left">
<bold>Asp-Arg-</bold>Asp-Glu</td>
<td valign="top" align="left">HLA-B27</td>
<td valign="top" align="left">Glu-Thr-<bold>Asp-Arg</bold>-Glu-Asp</td>
</tr>
<tr>
<td valign="top" align="left">Pul-A</td>
<td valign="top" align="left">
<bold>Gly-X-Pro</bold>
</td>
<td valign="top" align="left">Collagens type I, III and IV</td>
<td valign="top" align="left">
<bold>Gly-X-Pro</bold>
</td>
</tr>
<tr>
<td valign="top" colspan="2" align="left">
<italic>P. mirabilis</italic>
</td>
<td valign="top" colspan="2" align="left"/>
</tr>
<tr>
<td valign="top" align="left">Hemolysin</td>
<td valign="top" align="left">Glu-Ser-<bold>Arg-Arg-Ala</bold>-Leu</td>
<td valign="top" align="left">HLA-DR1/4</td>
<td valign="top" align="left">Glu-Gln-<bold>Arg-Arg-Ala</bold>-Ala</td>
</tr>
<tr>
<td valign="top" align="left">Urease</td>
<td valign="top" align="left">Leu-<bold>Arg-Arg-Glu</bold>-Iso</td>
<td valign="top" align="left">Collagen type XI</td>
<td valign="top" align="left">Iso-<bold>Arg-Arg-Glu</bold>-Thr</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>*amino acids sequences common for the bacterial antigen and appropriate self-antigen are bolded.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s3">
<title>3 The virulence factors with similar features observed for <italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> strains</title>
<p>
<italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> along with <italic>Escherichia coli</italic> are the most common causes of UTI cases, both community- and hospital-acquired ones (<xref ref-type="bibr" rid="B89">Oloomi et&#xa0;al., 2020</xref>). The first two species contribute to recurrent UTIs, which derives from their multidrug-resistance (<xref ref-type="bibr" rid="B45">Hooton, 2001</xref>). These facts and co-isolation of both species from polymicrobial infections increase the interest in the similarities between virulence factors of <italic>K. pneumoniae</italic> and <italic>P. mirabilis</italic> (<xref ref-type="bibr" rid="B78">Macleod and Stickler, 2007</xref>; <xref ref-type="bibr" rid="B38">Galv&#xe1;n et&#xa0;al., 2016</xref>). Many factors including: adhesins, siderophores, protein toxins, proteinases, ureases are implicated in the virulence of the representatives of both species, and a few have much in common in their structure and functions (<xref ref-type="bibr" rid="B73">Lindberg et&#xa0;al., 1975</xref>; <xref ref-type="bibr" rid="B30">Dutton et&#xa0;al., 1978</xref>; <xref ref-type="bibr" rid="B51">Joseleau et&#xa0;al., 1978</xref>; <xref ref-type="bibr" rid="B52">Joseleau and Marais, 1979</xref>; <xref ref-type="bibr" rid="B115">Sidorczyk et&#xa0;al., 1983</xref>; <xref ref-type="bibr" rid="B53">Joseleau and Marais, 1988</xref>; <xref ref-type="bibr" rid="B50">Jansson et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B35">Erbing et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B82">Mobley et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B43">Helander et&#xa0;al., 1996</xref>; <xref ref-type="bibr" rid="B101">Podschun and Ullmann, 1998</xref>; <xref ref-type="bibr" rid="B87">O&#x2019;Hara et&#xa0;al., 2000</xref>; <xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B44">Holst, 2007</xref>; <xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B108">R&#xf3;&#x17c;alski et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B60">Konieczna et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B64">Kubler-Kielb et&#xa0;al., 2013</xref>). Urease, LPS and capsule polysaccharides will be discussed in detail in the next chapters as the virulence factors with the highest number of features common to both species (<xref ref-type="bibr" rid="B73">Lindberg et&#xa0;al., 1975</xref>; <xref ref-type="bibr" rid="B30">Dutton et&#xa0;al., 1978</xref>; <xref ref-type="bibr" rid="B51">Joseleau et&#xa0;al., 1978</xref>; <xref ref-type="bibr" rid="B52">Joseleau and Marais, 1979</xref>; <xref ref-type="bibr" rid="B115">Sidorczyk et&#xa0;al., 1983</xref>; <xref ref-type="bibr" rid="B53">Joseleau and Marais, 1988</xref>; <xref ref-type="bibr" rid="B50">Jansson et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B35">Erbing et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B82">Mobley et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B43">Helander et&#xa0;al., 1996</xref>; <xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B44">Holst, 2007</xref>; <xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B60">Konieczna et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B64">Kubler-Kielb et&#xa0;al., 2013</xref>).</p>
<sec id="s3_1">
<title>3.1 Urease as the non-polysaccharide virulence factor with similar features observed for <italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> strains</title>
<p>Urease is the nickel containing enzyme catalyzing the hydrolysis of urea to yield ammonia and carbon dioxide. Ammonia has been found to damage the tissues and elevate urine pH resulting in crystallization of magnesium and calcium ions, which contributes to stone formation (<xref ref-type="bibr" rid="B80">Maroncle et&#xa0;al., 2006</xref>). In <italic>Klebsiella</italic> spp. urease is localized in cytoplasm and in <italic>P. mirabilis</italic> it is present in periplasm or in the outer membrane. <italic>P. mirabilis</italic> urease is induced by the presence of urea and <italic>K. pneumoniae</italic> urease &#x2013; by the presence of poor nitrogen sources (<xref ref-type="bibr" rid="B82">Mobley et&#xa0;al., 1995</xref>).</p>
<p>Urease is a non-polysaccharide virulence factor, which shows structural similarities in both <italic>Klebsiella</italic> spp. and <italic>Proteus</italic> spp (<xref ref-type="bibr" rid="B82">Mobley et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B116">Stickler et&#xa0;al., 1998</xref>; <xref ref-type="bibr" rid="B108">R&#xf3;&#x17c;alski et&#xa0;al., 2012</xref>). Similarities have been found in gene sequences in urease gene clusters (<italic>ureDABCEFG</italic>) in <italic>K. aerogenes</italic> and <italic>P. mirabilis</italic>. In contrast to <italic>K. aerogenes</italic> genome, in the <italic>P. mirabilis</italic> genome <italic>ureR</italic> gene (<italic>ureR</italic>-dependent promoter) was additionally detected - upstream of <italic>ureD</italic> (<xref ref-type="bibr" rid="B82">Mobley et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B47">Island and Mobley, 1995</xref>; <xref ref-type="bibr" rid="B18">Coker et&#xa0;al., 2000</xref>). The <italic>ureR</italic> regulates the urease expression in <italic>Proteus</italic> spp., and in <italic>Klebsiella</italic> spp. this role is played by the nitrogen regulatory system (NTR). Predicted molecular sizes of appropriate ure-encoded polypeptides are also similar in <italic>K. aerogenes</italic> [1] and in <italic>P. mirabilis</italic> [2]:</p>
<list list-type="simple">
<list-item>
<p>[1] UreA 11.1 kDa, UreB 11.7 kDa, UreC 60.3 kDa, UreE 17.6 kDa, UreF 25.2 kDa, UreG 21.9 kDa;</p>
</list-item>
<list-item>
<p>[2] UreA 11.0 kDa, UreB 12.2 kDa, UreC 61.0 kDa, UreE 17.9 kDa, UreF 23.0 kDa, UreG 22.4 kDa (<xref ref-type="bibr" rid="B82">Mobley et&#xa0;al., 1995</xref>).</p>
</list-item>
</list>
<p>The protein sequence of the UreC subunit from <italic>K. aerogenes</italic> is 72% identical to the UreC sequence from <italic>P. mirabilis</italic> (<xref ref-type="bibr" rid="B82">Mobley et&#xa0;al., 1995</xref>). Although urease is regarded as a conservative enzyme and its structure is similar for different bacteria, except <italic>Helicobacter pylori</italic> or <italic>Staphylococcus cohnii</italic>, the numbers of amino acids of particular polypeptides and the structure of the flap region in ureases of <italic>P. mirabilis</italic> and <italic>K. aerogenes</italic> show the highest homology. From the protein products of <italic>ure</italic> genes described for <italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> the highest similarities were observed for UreD [274 amino acids], UreG [205], &#x3b1; [567] and &#x3b3; [100] (<xref ref-type="bibr" rid="B60">Konieczna et&#xa0;al., 2012</xref>).</p>
<p>More divergences noted for <italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> urease concerned its activity. The latter species has been reported to hydrolyze urea ten times slower than the former one (<xref ref-type="bibr" rid="B116">Stickler et&#xa0;al., 1998</xref>). Other studies using different solid media have also confirmed that correlation, i.e. the onset of urease reaction appeared after 9-10 h in the case of <italic>Klebsiella</italic> spp. strains and after 1-2 h for <italic>Proteus</italic> spp. (<xref ref-type="bibr" rid="B129">Vuye and Pijck, 1973</xref>). Some <italic>Klebsiella</italic> sp. strains are urease-negative, but they were found to enhance the <italic>P. mirabilis</italic> urease activity in the <italic>K</italic>. <italic>p</italic>. &#x2013; <italic>P</italic>. <italic>m</italic>. coculture experiment (<xref ref-type="bibr" rid="B7">Armbruster et&#xa0;al., 2017</xref>). The underlying mechanism of enhanced urease activity of one strain by another may decrease the risk of development of complications in polymicrobial CAUTIs (<xref ref-type="bibr" rid="B7">Armbruster et&#xa0;al., 2017</xref>), thus elimination of one bacterial species may weaken the urease activity of the representatives of other species.</p>
<p>As was mentioned before, urease activity is connected with urinary stones occurrence. <italic>Proteus</italic> spp. is one of the most common pathogens inducing the formation of bladder and kidney stones, mainly struvite ones. Although <italic>Klebsiella</italic> spp. are mentioned as urease producing pathogens, also isolated from patients with urinary stones (mainly calculi containing oxalate and calcium phosphate) (<xref ref-type="bibr" rid="B11">Bichler et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B118">Torzewska et&#xa0;al., 2014</xref>), they have been found to produce none or little catheter encrustation and not to elevate urinary pH above 7.0 (<xref ref-type="bibr" rid="B116">Stickler et&#xa0;al., 1998</xref>; <xref ref-type="bibr" rid="B14">Broomfield et&#xa0;al., 2009</xref>). However, <italic>K. pneumoniae</italic> is known to produce mucoid plugs in the catheter lumen (<xref ref-type="bibr" rid="B14">Broomfield et&#xa0;al., 2009</xref>). <italic>P. mirabilis</italic> have been demonstrated to cause crystallization within the human ureter and bladder epithelial cells (<xref ref-type="bibr" rid="B118">Torzewska et&#xa0;al., 2014</xref>). It has been shown that the crystallization process may be enhanced (<italic>P. vulgaris</italic> O12) or inhibited (<italic>P. mirabilis</italic> O28 and O47) by the <italic>Proteus</italic> lipopolysaccharides (LPSs) depending on their O-polysaccharides (OPSs) structures and their affinity for Ca<sup>2+</sup> and Mg<sup>2+</sup> cations (<xref ref-type="bibr" rid="B119">Torzewska et&#xa0;al., 2003</xref>). Despite the role of bacterial urease in UTIs development, the metabolism of urea has also been demonstrated to be important in the gastro intestinal tract colonization by <italic>K. pneumoniae</italic> (<xref ref-type="bibr" rid="B80">Maroncle et&#xa0;al., 2006</xref>).</p>
<p>Urease is also produced by other <italic>Enterobacterales</italic> which are a part of human intestinal microflora but the level of the enzyme activity is species-specific and varies with the medium used (<xref ref-type="bibr" rid="B129">Vuye and Pijck, 1973</xref>). For example, among <italic>Escherichia coli</italic> strains, only 1% have been identified as urease-positive (<xref ref-type="bibr" rid="B60">Konieczna et&#xa0;al., 2012</xref>). <italic>Citrobacter</italic> and <italic>Enterobacter</italic> spp. are characterized as those with irregular urease activity. Among urease-positive <italic>Serratia</italic> spp. strains, urease action is delayed more than in the case of <italic>Klebsiella</italic> spp. strains (<xref ref-type="bibr" rid="B129">Vuye and Pijck, 1973</xref>). Despite the fact that <italic>Providencia morganii</italic> and <italic>P. rettgeri</italic> are regarded to be as effective urease producers as <italic>P. mirabilis</italic>, the urease activity, structure and genetic organization of the enzyme genes are well-known for <italic>Klebsiella</italic> and <italic>Proteus</italic> spp. frequently isolated from polymicrobial UTIs (<xref ref-type="bibr" rid="B82">Mobley et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B60">Konieczna et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B38">Galv&#xe1;n et&#xa0;al., 2016</xref>).</p>
</sec>
<sec id="s3_2">
<title>3.2 Polysaccharide virulence factors with similar features observed for <italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> strains</title>
<sec id="s3_2_1">
<title>3.2.1 Lipopolysaccharide</title>
<p>LPS is an essential component of the outer membrane of all Gram-negative bacteria and their major virulence factor. Due to its biological activity, LPS is regarded as an endotoxin. During infection it is released from bacterial cells to the blood where it is bound to LPS binding protein (LBP) and through CD14 and TLR4 (Toll-like receptor) induces macrophages to the pro-inflammatory cytokines secretion. Over-stimulation of the process leads to endotoxic shock development (<xref ref-type="bibr" rid="B102">Poxton, 1995</xref>). LPS exhibits many biological activities and its parts interact with bacterial or eukaryotic cells, <italic>e.g</italic>. O-polysaccharides chains, most outstanding from the bacterial cell, are involved in glycocalyx formation or make the bacteria resistant to the active membrane attack complex (<xref ref-type="bibr" rid="B102">Poxton, 1995</xref>; <xref ref-type="bibr" rid="B108">R&#xf3;&#x17c;alski et&#xa0;al., 2012</xref>). It is worth mentioning that LPS is highly immunogenic and its parts induce the production of antibodies of different specificity, which is important in searching for broadly cross-reacting immunoglobulins (<xref ref-type="bibr" rid="B102">Poxton, 1995</xref>).</p>
<p>Smooth (S) forms of <italic>Proteus</italic> spp. and <italic>Klebsiella</italic> spp. bacteria produce LPS consisting of three parts differing in their chemical structures and biological functions: lipid A, a core region and an OPS (<xref ref-type="bibr" rid="B124">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B92">Palusiak, 2013</xref>).</p>
<sec id="s3_2_1_1">
<title>3.2.1.1 Lipid A</title>
<p>Lipid A anchors LPS in the outer leaflet of the bacterial outer membrane (<xref ref-type="bibr" rid="B102">Poxton, 1995</xref>). Lipid A is structurally the most conserved region of LPS among Gram-negative bacteria and in <italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> bacilli the lipid A structures are almost identical (<xref ref-type="bibr" rid="B115">Sidorczyk et&#xa0;al., 1983</xref>; <xref ref-type="bibr" rid="B43">Helander et&#xa0;al., 1996</xref>).</p>
<p>The lipid A structure of <italic>Proteus</italic> spp. LPS has been established for the deep rough R45 mutant of the <italic>P. mirabilis</italic> S1959 strain (<xref ref-type="bibr" rid="B115">Sidorczyk et&#xa0;al., 1983</xref>). The lipid A structure of <italic>Klebsiella</italic> spp. LPS was characterized in 1996 for the polymyxin-resistant <italic>K. pneumoniae</italic> O3 mutant OM-5 and its polymyxin-sensitive parent strain (LEN-1) (<xref ref-type="bibr" rid="B43">Helander et&#xa0;al., 1996</xref>). <italic>P. mirabilis</italic> R45, <italic>K. pneumoniae</italic> LEN-1 and OM-5 lipids A are similar in the fatty acids arrangement and composition. All contain seven fatty acids residues (heptaacylated lipid A) including four 3-hydroxytetradecanoic acids (3-OH-C<sub>14</sub>) attached directly to the backbone (bisphosporylated &#x3b2;(1&#x2192;6) linked GlcN disaccharide), two tetradecanoic acids ester-linked to 3-OH-C<sub>14</sub> linked to the nonreducing GlcN residue and one hexadecanoic acid that partially substitutes the hydroxyl group of 3-OH-C<sub>14</sub> acid present at position 2 of reducing GlcN (<xref ref-type="bibr" rid="B62">Kote&#x142;ko, 1986</xref>; <xref ref-type="bibr" rid="B43">Helander et&#xa0;al., 1996</xref>). For <italic>K</italic>. <italic>pneumoniae</italic> and <italic>P</italic>. <italic>mirabilis</italic> the hexaacylated species of lipids A (without hexadecanoic acid) have also been observed. In lipid A of LPSs from both species the ester-bound phosphate residue is substituted by 4-amino-4-deoxy-L-arabinopyranose (L-Ara<italic>p</italic>4N). The feature, which probably distinguishes <italic>P. mirabilis</italic> R45 lipid A of LPS from lipids A of <italic>K. pneumoniae</italic> LEN-1 and OM-5 LPSs is a free glycosidically bound phosphate group, which in <italic>K. pneumoniae</italic> lipid A is substituted by L-Ara<italic>p</italic>4N (<xref ref-type="bibr" rid="B62">Kote&#x142;ko, 1986</xref>; <xref ref-type="bibr" rid="B43">Helander et&#xa0;al., 1996</xref>). However, L-Ara<italic>p</italic>4N may be bound to the glycosidic phosphate group in a labile diester linkage, which could be cleaved under strong alkaline conditions. Thus, the structural analysis of <italic>P. mirabilis</italic> R45 LPS indicates only the putative substitution of a glycosidic phosphate residue by a pentosamine residue (<xref ref-type="bibr" rid="B128">Vinogradov et&#xa0;al., 1994</xref>). In <italic>K. pneumoniae</italic> LEN-1 and OM-5, the L-Ara<italic>p</italic>4N is linked to both phosphates of the lipid A backbone. However, the degree of substitution of phosphates by L-Ara<italic>p</italic>4N in both LPSs is remarkably different (<xref ref-type="bibr" rid="B43">Helander et&#xa0;al., 1996</xref>).</p>
<p>Lipid A of <italic>Proteus</italic> spp. as well as of other <italic>Enterobacterales</italic> ord. nov. is linked to the core region by a hydroxyl group at C6&#x2019; of a nonreducing GlcN residue (<xref ref-type="bibr" rid="B62">Kote&#x142;ko, 1986</xref>).</p>
</sec>
<sec id="s3_2_1_2">
<title>3.1.1.2 The core oligosaccharide of LPS</title>
<p>Comparison of the structures of the LPS core regions in all tested <italic>Proteus</italic> spp. and <italic>K. pneumoniae</italic> strains shows that they share a common heptasaccharide fragment, which includes:</p>
<list list-type="simple">
<list-item>
<p>&#x27a2; a disaccharide of 3-deoxy-&#x3b1;-D-<italic>manno</italic>-oct-2-ulosonic acid (&#x3b1;-Kdo; A, B);</p>
</list-item>
<list-item>
<p>&#x27a2; a trisaccharide of L-<italic>glycero</italic>-&#x3b1;-D-<italic>manno</italic>-heptose (&#x3b1;-Hep; C, D, E);</p>
</list-item>
<list-item>
<p>&#x27a2; &#x3b2;-glucose (&#x3b2;-Glc; F) residue linked to &#x3b1;-Hep C at O (4);</p>
</list-item>
<list-item>
<p>&#x27a2; an &#x3b1;-galacturonic acid (&#x3b1;-GalA; G) residue linked to &#x3b1;-Hep D at O (3) (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>) (<xref ref-type="bibr" rid="B126">Vinogradov et&#xa0;al., 2000</xref>; <xref ref-type="bibr" rid="B125">Vinogradov and Perry, 2001</xref>; <xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B107">Regu&#xe9; et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B44">Holst, 2007</xref>; <xref ref-type="bibr" rid="B123">Vinogradov, 2011</xref>).</p>
</list-item>
</list>
<p>This heptasaccharide fragment is also a part of the LPS core region of two <italic>Serratia marcescens</italic> strains (<xref ref-type="bibr" rid="B44">Holst, 2007</xref>; <xref ref-type="bibr" rid="B92">Palusiak, 2013</xref>).</p>
<p>Other common residues which can be found in all tested LPS core regions of <italic>K. pneumoniae</italic> and some <italic>P. mirabilis</italic> strains, are: &#x3b1;-GlcN (H) attached to the &#x3b1;-GalA (G) residue at O4 and &#x3b2;-GalA (I/R<sup>3</sup>) linked to Hep (E) at O (7) (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>) (<xref ref-type="bibr" rid="B126">Vinogradov et&#xa0;al., 2000</xref>; <xref ref-type="bibr" rid="B125">Vinogradov and Perry, 2001</xref>; <xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B107">Regu&#xe9; et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B44">Holst, 2007</xref>; <xref ref-type="bibr" rid="B123">Vinogradov, 2011</xref>). A component common for <italic>P. mirabilis</italic> (O27) (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1B</bold>
</xref>) and <italic>K. pneumoniae</italic> (O1, O2a, O2a,c, O3-O5, O8, O12) LPS core regions (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1C</bold>
</xref>) is GalA (J) substituting &#x3b2;-Glc (F) at O (6) (non-stoichiometric substitution) (<xref ref-type="bibr" rid="B125">Vinogradov and Perry, 2001</xref>; <xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B44">Holst, 2007</xref>). Major structural differences between LPS core regions of <italic>P. mirabilis</italic> and <italic>K. pneumoniae</italic> strains concern the outer core region (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>) (<xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B107">Regu&#xe9; et&#xa0;al., 2005</xref>).</p>
<p>It is worth mentioning that over 21 different structures of the outer core region have been determined in <italic>Proteus</italic> spp., among which eight have been characterized for <italic>P. mirabilis</italic> strains. These structures are mainly linear or branched (<italic>P. mirabilis</italic> O48) and contain from two to four sugar residues, some of which are acylated (<xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B123">Vinogradov, 2011</xref>). In <italic>K. pneumoniae</italic> only two structures of the LPS core region differing in the substituents of &#x3b1;-GlcN (H) have been described (<xref ref-type="fig" rid="f1">
<bold>Figures&#xa0;1C, D</bold>
</xref>) (<xref ref-type="bibr" rid="B125">Vinogradov and Perry, 2001</xref>; <xref ref-type="bibr" rid="B107">Regu&#xe9; et&#xa0;al., 2005</xref>). Neither LD-Hep nor &#x3b1;-Kdo, present in the outer core region of <italic>K. pneumoniae</italic> LPSs (type 1 core) (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1C</bold>
</xref>), has ever been found in this part of <italic>Proteus</italic> spp. LPSs (<xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B123">Vinogradov, 2011</xref>). Also, the <italic>P. mirabilis</italic> LPS outer core region may contain components which are not found in the <italic>K. pneumoniae</italic> LPS core region <italic>e.g.</italic> cyclic acetal formed by an 2-acetamido-2-deoxy-D-galactose residue in the open-chain form (Gal<italic>o</italic>NAc) linked to O (4) and O (6) of the neighboring GalN residue (<italic>P. mirabilis</italic> O27) (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1B</bold>
</xref>) (<xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>).</p>
<p>The great structural heterogeneity of <italic>Proteus</italic> spp. LPS core regions does not result from the differences only in the outer core region but also in the inner core region, which is in general more structurally conserved in other <italic>Enterobacterales</italic> ord. nov. LPSs (<xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B92">Palusiak, 2013</xref>).</p>
<p>In contrast to <italic>K. pneumoniae</italic> LPSs, three glycoforms differing in two substituents R<sup>2</sup> (&#x3b1;-DD-Hep-(1&#x2192;2)-&#x3b1;-DD-Hep, &#x3b1;-DD-Hep or H) and R<sup>3</sup> (&#x3b2;-GalA or H) have been determined for the inner core region of <italic>Proteus</italic> spp. LPSs. The majority of <italic>P. mirabilis</italic> LPSs tested so far have presented glycoform II of their inner core region (<xref ref-type="fig" rid="f1">
<bold>Figures&#xa0;1A, B</bold>
</xref>) (<xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B59">Kondakova et&#xa0;al., 2005</xref>). What is more interesting, multiple structural variants of the <italic>P. mirabilis</italic> core region may appear even within the LPS of one strain <italic>e.g.</italic> two types of the core region in <italic>P. mirabilis</italic> O27 (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1B</bold>
</xref>) and four different R<sup>1</sup> (<italic>P</italic>Etn), R<sup>2</sup>, R<sup>3</sup> combinations in the <italic>P. mirabilis</italic> O3 LPS core region (<xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>), which does not occur in the case of <italic>K. pneumonia</italic> (<xref ref-type="bibr" rid="B44">Holst, 2007</xref>).</p>
<p>The core region of the <italic>P. mirabilis</italic> O27 LPS is similar to the core region of <italic>K. pneumoniae</italic> LPS due to the lack of L-Ara<italic>p</italic>4N linked to the Kdo (A) residue at O (8) (<xref ref-type="fig" rid="f1">
<bold>Figures&#xa0;1B&#x2013;D</bold>
</xref>) (<xref ref-type="bibr" rid="B107">Regu&#xe9; et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B44">Holst, 2007</xref>). L-Ara<italic>p</italic>4N occurs at this position in the other tested <italic>Proteus</italic> spp. LPSs (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1A</bold>
</xref>) (<xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>) and has been found to play a crucial role in the decreased binding of polymyxin B (<xref ref-type="bibr" rid="B12">Boll et&#xa0;al., 1994</xref>).</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
  <p>Structures of the core regions of: <bold>(A)</bold> <italic>P. mirabilis</italic> R110; <bold>(B)</bold> <italic>P. mirabilis</italic> O27; <bold>(C)</bold> <italic>K. pneumoniae</italic> from O1, O2a, O2a,c, O3-O5, O8 and O12 serotypes; <bold>(D)</bold> <italic>K</italic>. <italic>pneumoniae</italic> from the O1:K2 serotype (<xref ref-type="bibr" rid="B126">Vinogradov et&#xa0;al., 2000</xref>; <xref ref-type="bibr" rid="B125">Vinogradov and Perry, 2001</xref>; <xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B107">Regu&#xe9; et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B44">Holst, 2007</xref>). The outer core region <bold>(R)</bold> is indicated by the frame. Ara<italic>p</italic>4N, 4-amino-4-deoxy-L-arabinopyranose; GalA, galacturonic acid; GalAN, GalA amidated by aliphatic polyamines; GalN, galctosamine; Gal<italic>o</italic>NAc, open-chain of GalNAc; Glc, glucose; GlcN, glucosamine; GlcNAc, 2-acetamido-2-deoxy-D-galactose; LD-Hep, L-<italic>glycero</italic>-D-<italic>manno</italic>-heptose; DD-Hep, D-<italic>glycero</italic>-D-<italic>manno</italic>-heptose; Kdo, 3-deoxy-D-<italic>manno</italic>-oct-2-ulosonic acid; <italic>P</italic>Etn,2-aminoethyl phosphate.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-12-991657-g001.tif"/>
</fig>
</sec>
<sec id="s3_2_1_3">
<title>3.1.1.3 O-polysaccharide of LPS</title>
<p>To date, the O-antigen linkage in <italic>Proteus</italic> spp. LPS has not been precisely determined. However, the R substituent of the core region (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>) is indicated as a possible linkage site of OPS (<xref ref-type="bibr" rid="B127">Vinogradov et&#xa0;al., 2002</xref>). The <italic>K. pneumoniae</italic> type 1 core oligosaccharide is linked to OPS <italic>via</italic> O-5 of the Kdo residue from the outer core region (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1C</bold>
</xref>) (<xref ref-type="bibr" rid="B124">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B44">Holst, 2007</xref>). This Kdo residue is a part of the linkage region, which is common to all tested <italic>K. pneumoniae</italic> O antigens (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1C</bold>
</xref>), the bolded fragment. The primer &#x3b2;-GlcNAc residue forming the linkage region is derived from the O-chain biosynthesis pathway and is substituted by a repeating unit of the majority of <italic>K. pneumoniae</italic> O antigens or by the bridging disaccharide 3)-(&#x3b1;-Man-(1&#x2192;3)-&#x3b1;-Man) in <italic>K. pneumoniae</italic> O3 and O5 OPSs (<xref ref-type="fig" rid="f2">
<bold>Figures&#xa0;2D, E</bold>
</xref>) (<xref ref-type="bibr" rid="B124">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B57">Knirel, 2011</xref>). In <italic>K. pneumoniae</italic> strain 52145 from serotype O1:K2 (type 2 OS) (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1D</bold>
</xref>) the last Glc outer-core residue has been suggested to be a linkage site of OPS (<xref ref-type="bibr" rid="B107">Regu&#xe9; et&#xa0;al., 2005</xref>).</p>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>Structures of <italic>K. pneumoniae</italic> O-polysaccharides <bold>(A&#x2013;K)</bold> and of those <italic>P. mirabilis</italic> OPSs <bold>(L-P)</bold>, which have the components common with the selected <italic>K. pneumoniae</italic> OPSs (<xref ref-type="bibr" rid="B57">Knirel, 2011</xref>; <xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>). The residues which do not belong to the repeating units are underlined. Gal<italic>f</italic>, galactofuranose; Gal<italic>p</italic>, galactopyranose; Glc, glucose; GlcNAc 2-acetamido-2-deoxy-D-galactose; GalA, galacturonic acid; D-GalNAc, 2-acetamido-2-deoxy-D-galactose; D-Gro-1-<italic>P</italic>, D-glycerol 1-phosphate; Kdo, 3-deoxy-D-<italic>manno</italic>-oct-2-ulosonic acid; Man, mannose; Pyr &#x2013; pyruvic acid; Rha, ramnose; Rib<italic>f</italic>, ribofuranose; Suc, succinic acid; Qui4n, 4-amino-4-deoxy-D-quinovose.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-12-991657-g002.tif"/>
</fig>
<p>The OPS of <italic>P. mirabilis</italic> is definitely more structurally heterogenous than that of <italic>K. pneumoniae</italic>. For <italic>P. mirabilis</italic> strains, 49 different OPS structures have been determined and some of them (<italic>e.g. P. mirabilis</italic> O69 OPS) are common to other representatives of the genus (<xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B29">Drzewiecka et&#xa0;al., 2016a</xref>; <xref ref-type="bibr" rid="B26">Drzewiecka et&#xa0;al., 2016b</xref>). The OPS structures of the most <italic>Proteus</italic> strains tested so far have been already gathered and presented in a review by <xref ref-type="bibr" rid="B58">Knirel et&#xa0;al. (2011)</xref> (<xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>). Therefore, in this review only structures of OPSs, which share common fragments with <italic>Klebsiella</italic> CPSs are presented (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3</bold>
</xref>).</p>
<fig id="f3" position="float">
<label>Figure&#xa0;3</label>
<caption>
<p>Structures of <italic>K. pneumoniae</italic> capsular polysaccharides and <italic>P. mirabilis</italic> OPSs <bold>(A&#x2013;E)</bold> sharing the common fragments (in frames) (<xref ref-type="bibr" rid="B73">Lindberg et&#xa0;al., 1975</xref>; <xref ref-type="bibr" rid="B30">Dutton et&#xa0;al., 1978</xref>; <xref ref-type="bibr" rid="B51">Joseleau et&#xa0;al., 1978</xref>; <xref ref-type="bibr" rid="B52">Joseleau and Marais, 1979</xref>; <xref ref-type="bibr" rid="B53">Joseleau and Marais, 1988</xref>; <xref ref-type="bibr" rid="B50">Jansson et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B35">Erbing et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B64">Kubler-Kielb et&#xa0;al., 2013</xref>). Dotted lines indicate that some of the residues are <italic>O</italic>-acetylated. Cho<italic>P</italic>, choline phosphate; Etn<italic>P</italic>, ethanolamine phosphate; Fuc, fucose; D-Fuc3N, 3-amino-3-deoxy-D-fucose; Gal<italic>f</italic>, galactofuranose; Gal<italic>p</italic>, galactopyranose; GalA, galacturonic acid; Glc, glucose; GlcA, glucuronic acid; D-GlcNAc, 2-acetamido-2-deoxy-D-glucose; L-Lys, L-lysine; Man, mannose; Pyr &#x2013; pyruvic acid; <italic>R</italic>-3HOBu, (<italic>R</italic>)-3-hydroxybutanoic acid; <italic>R</italic>-Cet-Etn<italic>P</italic>, <italic>N</italic>-[(<italic>R</italic>)-1-carboxyethyl]ethanolamine phosphate; Rha, ramnose; L-Ser, L-serine; Suc, succinic acid; Sug, 4-deoxy-<italic>threo</italic>-hex-4-enopyranosyluronic acid group; Qui4N, 4-amino-4-deoxy-D-quinovose.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-12-991657-g003.tif"/>
</fig>
<p>In <italic>K. pneumoniae</italic> only 13 OPS structures have been determined (<xref ref-type="bibr" rid="B57">Knirel, 2011</xref>). Most OPS structures presented by <italic>P. mirabilis</italic> strains are branched, and in <italic>K. pneumoniae</italic> LPSs the lateral substituent appears only in two OPS structures (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2A</bold>
</xref>) (<xref ref-type="bibr" rid="B57">Knirel, 2011</xref>; <xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>). <italic>P. mirabilis</italic> OPSs consist of repeating units comprising from three to seven sugar and non-sugar components and <italic>K. pneumoniae</italic> repeating units include from two to five sugar components. <italic>Proteus</italic> spp. OPSs are heteropolysaccharides, whereas, among <italic>K. pneumoniae</italic> O-antigens, homopolysaccharides also occur (<italic>e.g.</italic> O3, O5, 22535) (<xref ref-type="fig" rid="f2">
<bold>Figures&#xa0;2D&#x2013;F</bold>
</xref>). Homopolymers are also present in <italic>K. pneumoniae</italic> OPSs in a form of galactan I: 3)-&#x3b1;-Gal<italic>p</italic>-(1&#x2192;3)-&#x3b2;-Gal<italic>f</italic>(1-, which forms the repeating units alone (e.g. O2a, O2a,b OPSs (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2A</bold>
</xref>) or together with galactan II: 3)-&#x3b2;-Gal<italic>p</italic>-(1&#x2192;3)-&#x3b1;-Gal<italic>p</italic>(1- (O1, O6 and O8) (<xref ref-type="fig" rid="f2">
<bold>Figures&#xa0;2B, C</bold>
</xref>) (<xref ref-type="bibr" rid="B57">Knirel, 2011</xref>). The latter is placed distally toward galactan I and defines the O1 serotype (<xref ref-type="bibr" rid="B124">Vinogradov et&#xa0;al., 2002</xref>).</p>
<p>The &#x3b2;-Gal or &#x3b1;-Gal residues are found in <italic>P. mirabilis</italic> OPSs quite frequently but contrary to the &#x3b2;-Gal residues in <italic>Klebsiella</italic> OPS, they always occur in a pyranose form. These residues are present in <italic>P. mirabilis</italic> OPSs as single Gal residues (<italic>P. mirabilis</italic> O75) (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2P</bold>
</xref>) or as Gal disaccharides but in a different sequence than in galactan II in <italic>K. pneumoniae</italic> OPS <italic>e.g.</italic> 3)-&#x3b1;-Gal<italic>p</italic>-(1&#x2192;6)-&#x3b2;-Gal<italic>p</italic>(1- (<italic>P. mirabilis</italic> O57) (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2O</bold>
</xref>) (<xref ref-type="bibr" rid="B124">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>).</p>
<p>Unlike <italic>P. mirabilis</italic> OPSs, the OPS chains of <italic>K. pneumoniae</italic> O4, O5, O11 and O12 antigens possess at their non-reducing ends residues that are not composed of the repeating units <italic>e.g.</italic> &#x3b1;-Kdo-(2&#x2192;2)-&#x3b2;-Rib<italic>f</italic> (O4), Me-3)&#x3b1;-Man (O5)  or &#x3b2;-Kdo-(2&#x2192;3)-&#x3b1;-Rha (O12) (<xref ref-type="fig" rid="f2">
<bold>Figures&#xa0;2E, H, J</bold>
</xref>) - underlined residues (<xref ref-type="bibr" rid="B124">Vinogradov et&#xa0;al., 2002</xref>). Kdo or Man residues have not been found in <italic>P. mirabilis</italic> OPSs so far (<xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>). Other repeating units structures of <italic>K. pneumoniae</italic> OPSs are heteropolymers (<xref ref-type="fig" rid="f2">
<bold>Figures&#xa0;2G&#x2013;K</bold>
</xref>) (<xref ref-type="bibr" rid="B124">Vinogradov et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B57">Knirel, 2011</xref>). The single components of the <italic>K. pneumoniae</italic> O12 OPS (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2J</bold>
</xref>) are also found in <italic>P. mirabilis</italic> OPSs: &#x3b1;-Rha-(1&#x2192;3)-&#x3b2;-D-GlcNAc(1- (<italic>P. mirabilis</italic> O49 and O75 or in O51, where &#x3b1;-Rha is 2-O-acetylated) (<xref ref-type="fig" rid="f2">
<bold>Figures&#xa0;2M, N, P</bold>
</xref>). Components similar to those found in the repeating units of the <italic>K. pneumoniae</italic> O4 and O11 antigens [4)-&#x3b1;-Gal-(1&#x2192;2)-&#x3b2;-Rib<italic>f</italic>(1-] (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2H</bold>
</xref>) have also been detected in the <italic>P. mirabilis</italic> O36 antigen: 2)-&#x3b2;-Rib<italic>f</italic>-(1&#x2192;4)-&#x3b2;-Gal(1- (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2L</bold>
</xref>) (<xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B57">Knirel, 2011</xref>).</p>
<sec id="s3_2_1_3_1">
<title>3.1.1.3.1 <italic>Klebsiella</italic> spp. and <italic>Proteus</italic> spp. O-typing schemes</title>
<p>The O-antigen determines the serological specificity of the S and SR forms of bacteria (<xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>). The classification scheme for <italic>Proteus</italic> spp. was founded by <xref ref-type="bibr" rid="B56">Kauffmann (1966)</xref> and included 49 different <italic>P. mirabilis</italic> and/or <italic>P. vulgaris</italic> O serogroups (<xref ref-type="bibr" rid="B56">Kauffmann, 1966</xref>). This scheme was completed by <xref ref-type="bibr" rid="B67">Larsson et&#xa0;al. (1978)</xref> (six <italic>P. mirabilis</italic> O-serogroups) (<xref ref-type="bibr" rid="B67">Larsson et&#xa0;al., 1978</xref>), by <xref ref-type="bibr" rid="B98">Penner and Hennessy (1980)</xref> (11 O-serogroups containing <italic>P. mirabilis</italic> or <italic>P. vulgaris</italic> strains) (<xref ref-type="bibr" rid="B98">Penner and Hennessy, 1980</xref>) and by other authors (O-serogroups consisting of different <italic>Proteus</italic> species or of one species) (<xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B54">Kaca et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B92">Palusiak, 2013</xref>; <xref ref-type="bibr" rid="B95">Palusiak et&#xa0;al., 2013</xref>). Currently, the <italic>Proteus</italic> O-antigen classification scheme includes 83 O-serogroups, among which 43 contain <italic>P. mirabilis</italic> strains (the majority of them contain <italic>P. mirabilis</italic> strains only and in eight O-serogroups there are also other representatives of the genus &#x2013; O8, O11, O13, O17, O23, O34, O54, O69 and O71) (<xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B29">Drzewiecka et&#xa0;al., 2016a</xref>; <xref ref-type="bibr" rid="B26">Drzewiecka et&#xa0;al., 2016b</xref>). O77-O82 serogroups were created from <italic>Proteus</italic> clinical isolates from the &#x141;&#xf3;d&#x17a; area (Central Poland) (<xref ref-type="bibr" rid="B28">Drzewiecka et&#xa0;al., 2021</xref>).</p>
<p>The serological classification of <italic>Klebsiella</italic> spp. strains was reported in 1940 by Kauffmann and &#xd8;rskov, who separated three O groups: 1, 2 (with 2A and 2B subgroups) and 3, among which the O1 group was the most numerous (<xref ref-type="bibr" rid="B90">&#xd8;rskov, 1954</xref>). Initially, 12 O-antigen serogroups were described but structural similarities and the cross-reactivities between some of them resulted in slight differences in the authors&#x2019; opinions on the <italic>Klebsiella</italic> O typing scheme (<xref ref-type="bibr" rid="B121">Trautmann et&#xa0;al., 1997</xref>; <xref ref-type="bibr" rid="B42">Hansen et&#xa0;al., 1999</xref>; <xref ref-type="bibr" rid="B124">Vinogradov et&#xa0;al., 2002</xref>). For example, <xref ref-type="bibr" rid="B121">Trautmann et&#xa0;al. (1997)</xref> described the <italic>Klebsiella</italic> O9 serogroup as a separate one but the investigation by <xref ref-type="bibr" rid="B42">Hansen et&#xa0;al. (1999)</xref> revealed that the LPS from the strain prototype for serogroup O9 was structurally and serologically identical to the LPS from the strain belonging to serogroup O2 (<xref ref-type="bibr" rid="B121">Trautmann et&#xa0;al., 1997</xref>; <xref ref-type="bibr" rid="B42">Hansen et&#xa0;al., 1999</xref>). Thus serogroup O9 was proposed to be treated as a part of serogroup O2 (<xref ref-type="bibr" rid="B42">Hansen et&#xa0;al., 1999</xref>). Trautmann suggested excluding serogroup O8 (together with O6) from the scheme since O8 antigens had been found to be serologically indistinguishable from O1 LPSs (<xref ref-type="bibr" rid="B121">Trautmann et&#xa0;al., 1997</xref>; <xref ref-type="bibr" rid="B120">Trautman et&#xa0;al., 2004</xref>). On the contrary, <xref ref-type="bibr" rid="B42">Hansen et&#xa0;al. (1999)</xref> presented serogroup O8 as a separate one, mentioning that genetic methods would help in the distinction between O1 and O8 representatives (<xref ref-type="bibr" rid="B42">Hansen et&#xa0;al., 1999</xref>).</p>
<p>Among <italic>Klebsiella</italic> spp. O serotypes, O1 (the most often), O2 and O5 dominated among clinical isolates from Japan, Germany, Denmark, Spain and the United States with the exception of blood isolates from the USA where O2 representatives dominated over O1 (<xref ref-type="bibr" rid="B121">Trautmann et&#xa0;al., 1997</xref>; <xref ref-type="bibr" rid="B42">Hansen et&#xa0;al., 1999</xref>; <xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>). As for <italic>Proteus</italic> spp., the O3 serogroup dominated among <italic>P. mirabilis</italic> isolates according to the studies described by Larsson. In most of the studies <italic>Proteus</italic> O10 and O30 serogroups were also frequently found (<xref ref-type="bibr" rid="B66">Larsson, 1984</xref>). The O78 serogroup was found to be the most numerous in the <italic>Proteus</italic> classification
  scheme and seemed to be prevalent among patients from the &#x141;&#xf3;d&#x17a; area (<xref ref-type="bibr" rid="B28">Drzewiecka et&#xa0;al., 2021</xref>). <italic>K. pneumoniae</italic> O2 is the most heterogenous serotype characterized by the presence of many partial antigens (<xref ref-type="fig" rid="f2">
<bold>Figures&#xa0;2A, G</bold>
</xref>), among which O2ab was detected in the majority of O1 and O2ab clinical isolates tested (<xref ref-type="bibr" rid="B132">Whitfield et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B121">Trautmann et&#xa0;al., 1997</xref>; <xref ref-type="bibr" rid="B120">Trautman et&#xa0;al., 2004</xref>). In the <italic>Proteus</italic> spp. classification scheme the most heterogenous serogroup containing <italic>P. mirabilis</italic> strains is O23 with two subgroups (O23a,b,c; O23a,b,d) and with two OPSs structural variants among O23a,b,c representatives (<xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>).</p>
<p>The <italic>Proteus</italic> spp. classification scheme is based on the structural and serological diversity of LPS OPSs (<xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>). In the <italic>Klebsiella</italic> spp. classification scheme the crucial role is played by the heat-stable K-antigens, which are more diverse (77 serotypes) than the OPS parts (<xref ref-type="bibr" rid="B101">Podschun and Ullmann, 1998</xref>). However, the huge number of K serotypes and serological cross-reactions among them limit the K serotyping (<xref ref-type="bibr" rid="B101">Podschun and Ullmann, 1998</xref>; <xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>).</p>
</sec>
</sec>
<sec id="s3_2_1_4">
<title>3.2.1.2 Capsular polysaccharide</title>
<p>Hydrophilic polysaccharide capsules (K antigens) are the first virulence factors described for the genus <italic>Klebsiella</italic> and they are the most thoroughly studied ones (<xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>). The capsule surrounds the entire cell protecting it from drying out, phagocytosis and killing by serum and is associated with the development of the later stages of complex biofilm. Capsules are acidic structures, built of repeating units with four to six sugars and produced by the majority of uropathogenic <italic>K. pneumoniae</italic> strains (<xref ref-type="bibr" rid="B111">Schembri et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>). The size of <italic>Klebsiella</italic> CPSs influences the bacterial virulence. In contrast to highly encapsulated <italic>K. pneumoniae</italic> KP1-O which has been found to be extremely virulent in the murine burn wound sepsis model, the strain KP1-T with a smaller capsule (approximately one-third of that KP1-O) appeared to be comparatively nonvirulent (<xref ref-type="bibr" rid="B19">Cryz et&#xa0;al., 1984</xref>). The virulence of <italic>K. pneumoniae</italic> strains is also associated with a CPS structure. In less virulent K7 and K21a capsular antigens, the repetitive sequence of mannose-&#x3b1;-2/3-mannose is recognized by mannose-&#x3b1;-2/3-mannose-specific lectin of macrophages, which leads to lectinophagocytosis. On the other hand, the lack of mannose-2/3-mannose structures in more virulent K2 strains protects them against this process (<xref ref-type="bibr" rid="B13">Brisse et al., 2006</xref>). The capsule is so important in <italic>K. pneumoniae</italic> virulence because it may also influence the other virulence factors activity. It has been shown on <italic>K. pneumoniae</italic> strain C105 and its non-capsulated derivative that capsule expression results in impeding biofilm formation on the abiotic surface and agglutination of yeast cells, both processes mediated by type 1 fimbriae. This phenomenon has been suggested to result from the direct physical interference between type 1 fimbriae and the capsule (<xref ref-type="bibr" rid="B111">Schembri et&#xa0;al., 2005</xref>). CPS has been found to be a dominating (63%) component of the extracellular toxic complex (ETC), which is also composed of LPS (30%) and protein (7%). It has been shown that pure ETC of <italic>K. pneumoniae</italic> K8 strain exerts the cytotoxic effect on the rat embryo fibroblast cell line and changes the cell morphology. Although LPS accounts for ECT toxicity, the ETC effectiveness depends on the presence of a sufficient cell-associated capsule protecting the cell from phagocytosis (<xref ref-type="bibr" rid="B4">Al-Jumaily et&#xa0;al., 2012</xref>).</p>
<p>Among 78 K serotypes, 25 are mainly found in <italic>Klebsiella</italic> spp. clinical isolates causing bacteremia and the K2 serotype is predominant, followed by K1, in all <italic>Klebsiella</italic> spp. clinical isolates causing UTI, pneumonia and bacteremia (<xref ref-type="bibr" rid="B101">Podschun and Ullmann, 1998</xref>; <xref ref-type="bibr" rid="B91">Paczosa and Mecsas, 2016</xref>). Also, the K2 serotype, together with K1, is common among hvKP strains causing CA-PLA (community-acquired pyogenic liver abscesses). However, hypervirulence of K2 hvKP strains is believed to be connected with an increased expression of capsular material (hypermucoviscous phenotype) associated with the <italic>rmpA</italic> gene (a regulator of the mucoid phenotype) rather than the capsule serotype (<xref ref-type="bibr" rid="B114">Shon et&#xa0;al., 2013</xref>). Hypercapsulation increases resistance to complement killing or human neutrophil protein 1 and lactoferrin. The prevalence of more virulent K1 and K2 phenotypes among clinical <italic>K. pneumonia</italic> isolates results from their better capacity of survival in tissues and a higher resistance to lectinophagocytosis (<xref ref-type="bibr" rid="B91">Paczosa and Mecsas, 2016</xref>). In contrast to clinical isolates, the K33 and K69 serotypes dominated among environmental strains (<italic>e.g.</italic> from surface waters) (<xref ref-type="bibr" rid="B100">Podschun et&#xa0;al., 2001</xref>). Recently, on the basis of CPS locus and K-locus (KL) arrangement, series KL101-KL149, KL151, KL153-KL155 and KL157-159 have been additionally discovered, however their sugar composition remains unknown (<xref ref-type="bibr" rid="B96">Patro and Rathinavelan, 2019</xref>).</p>
<p>In <italic>Proteus</italic> spp. only four CPS structures have been described (two for <italic>P. mirabilis</italic> and two for <italic>P. vulgaris</italic> strains) (<xref ref-type="bibr" rid="B10">Beynon et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B99">Perry and MacLean, 1994</xref>; <xref ref-type="bibr" rid="B103">Rahman et&#xa0;al., 1997</xref>; <xref ref-type="bibr" rid="B104">Rahman et&#xa0;al., 1999</xref>). <italic>Proteus</italic> spp. CPSs consist of three to four saccharide residues and, similarly to <italic>Klebsiella</italic> CPSs, are acidic (due to the presence of uronosyl residues <italic>e.g.</italic> &#x3b2;-D-GalA in <italic>P. mirabilis</italic> WT19 or &#x3b1;-D-GlcA in <italic>P. mirabilis</italic> ATCC 49565). The acidic CPS is believed to act as a lubricant facilitating the migration of <italic>Proteus</italic> spp. swarmer cells (<xref ref-type="bibr" rid="B103">Rahman et&#xa0;al., 1997</xref>). However, in the <italic>Proteus</italic> spp. serological classification scheme, CPS is not taken into account due to the discovery that the CPSs of the two tested <italic>P. mirabilis</italic> 49565 and <italic>P. vulgaris</italic> ATCC 49990 strains had the same structures as their LPSs O chains (<xref ref-type="bibr" rid="B10">Beynon et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B99">Perry and MacLean, 1994</xref>).</p>
<p>What is interesting, while analyzing the selected <italic>Klebsiella</italic> spp. CPSs and <italic>Proteus</italic> spp. OPSs structures, common fragments could be observed as shown in the frames (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3</bold>
</xref>) (<xref ref-type="bibr" rid="B73">Lindberg et&#xa0;al., 1975</xref>; <xref ref-type="bibr" rid="B30">Dutton et&#xa0;al., 1978</xref>; <xref ref-type="bibr" rid="B51">Joseleau et&#xa0;al., 1978</xref>; <xref ref-type="bibr" rid="B52">Joseleau and Marais, 1979</xref>; <xref ref-type="bibr" rid="B53">Joseleau and Marais, 1988</xref>; <xref ref-type="bibr" rid="B50">Jansson et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B35">Erbing et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B64">Kubler-Kielb et&#xa0;al., 2013</xref>). The first fragment (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3A</bold>
</xref>) is rather a common component of <italic>K. pneumoniae</italic> CPSs and it may be substituted by the lateral residue of &#x3b2;-D-GalA like in K8 (reference strain 1015) or K59 serotypes (<xref ref-type="bibr" rid="B73">Lindberg et&#xa0;al., 1975</xref>; <xref ref-type="bibr" rid="B35">Erbing et&#xa0;al., 1995</xref>). The mentioned K serotypes share the fragment, 3)- &#x3b2;-D-Glc<italic>p</italic>-(1&#x2192;3)-&#x3b2;-D-Gal<italic>p</italic>(1-, with two <italic>P. mirabilis</italic> O serotypes, however this structure was not found in OPS of other known O serotypes of the <italic>Enterobacterales</italic> LPSs (<xref ref-type="bibr" rid="B57">Knirel, 2011</xref>). The components of fragment 3a are also present in the LPS OPS of <italic>Providencia alcalifaciens</italic> O9, O23, <italic>Hafnia alvei</italic> or <italic>Edwardsiella ictaluri</italic> MT 104 but in a different sequence and conformation, which makes the fragment unique for <italic>P. mirabilis</italic> OPS and <italic>K. pneumoniae</italic> CPS. The more common fragments of polysaccharides from many different bacterial species share more cross-reactions between specific antibodies and common epitopes can be observed in serological studies (<xref ref-type="bibr" rid="B94">Palusiak, 2021</xref>). The &#x3b1;-L-Rha residues are common components of <italic>K. pneumoniae</italic> CPSs (<xref ref-type="fig" rid="f3">
<bold>Figures&#xa0;3B, C, E</bold>
</xref>) which are rarely found in <italic>Proteus</italic> OPSs (<italic>Proteus</italic> spp. O22, O32 or O75) (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2P</bold>
</xref>, <xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3E</bold>
</xref>) (<xref ref-type="bibr" rid="B53">Joseleau and Marais, 1988</xref>; <xref ref-type="bibr" rid="B9">Athamna et&#xa0;al., 1991</xref>; <xref ref-type="bibr" rid="B58">Knirel et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B64">Kubler-Kielb et&#xa0;al., 2013</xref>). The different rhamnose disaccharides are also commonly found in OPSs of other <italic>Enterobacterales</italic> LPSs like: <italic>Hafnia alvei</italic>, <italic>Citrobacter youngae</italic>, <italic>C. braakii</italic>, <italic>Escherichia hermannii</italic> (<xref ref-type="bibr" rid="B57">Knirel, 2011</xref>). The fragment 2)-&#x3b1;-L-Rha-(1&#x2192;2)-&#x3b1;-L-Rha(1-, depicted in <xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3E</bold>
</xref> as common for appropriate <italic>K. pneumoniae</italic> and <italic>Proteus mirabilis</italic> serotypes, is located in <italic>H. alvei</italic> 1222 OPS, where it is phosphorylated, in many <italic>Shigella flexneri</italic> O serotypes (<xref ref-type="bibr" rid="B57">Knirel, 2011</xref>).</p>
<p>The knowledge on polysaccharide fragments common to such a wide range of <italic>Enterobacterales</italic> would be helpful in obtaining broadly cross-reactive antibodies that would be also protective and, when given to patients, would neutralize LPS and prevent from septic shock development (<xref ref-type="bibr" rid="B102">Poxton, 1995</xref>). Another example of applying common polysaccharide fragments is ELISA construction where the fragments would be used as coated antigens recognized by specific antibodies from the patients sera. Such an assay, EndoCAB&#x2122;, was applied for screening blood donors for high levels of cross-reactive antibodies specific to LPS core regions of <italic>K. pneumoniae</italic>, <italic>E. coli</italic>, <italic>S. minnesota</italic> and <italic>Pseudomonas aeruginosa</italic> R-mutants used as antigens (<xref ref-type="bibr" rid="B102">Poxton, 1995</xref>).</p>
<p>Sharing common fragments of polysaccharides by representatives of different bacterial genera is meaningful in the development of a multivalent vaccine with a broad spectrum of cross-protection <italic>in vivo</italic>. Such a vaccine may contain whole bacterial cells (inactivated, attenuated or cell lysates), the whole antigens or their fragments (epitopes) (<xref ref-type="bibr" rid="B89">Oloomi et&#xa0;al., 2020</xref>).</p>
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</sec>
<sec id="s4">
<title>4 Vaccine formula based on <italic>K. pneumoniae</italic> and <italic>P. mirabilis</italic> antigens</title>
<p>There are three commercially available vaccines composed of inactivated enterobacterial strains, including <italic>K. pneumoniae</italic> and <italic>Proteus</italic> spp.: Uromune<sup>&#xae;</sup> (sublingual spray), Urovac<sup>&#xae;</sup> (administered <italic>via</italic> vaginal suppositories) and Urostim<sup>&#xae;</sup> (administered orally), whose administration to volunteers led to a reduction of recurrent UTIs with slight potential adverse reactions (<xref ref-type="bibr" rid="B86">Nenkov, 2000</xref>; <xref ref-type="bibr" rid="B122">Uehling et&#xa0;al., 2003</xref>; <xref ref-type="bibr" rid="B46">Hopkins et&#xa0;al., 2007</xref>; <xref ref-type="bibr" rid="B135">Yang and Foley, 2018</xref>). However, applying a whole cell vaccine may be associated with some disadvantages like the non-specific immune responses and toxicity of such formulations (<xref ref-type="bibr" rid="B89">Oloomi et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B8">Assoni et&#xa0;al., 2021</xref>). The subunit of <italic>K. pneumoniae</italic> vaccines containing CPSs as antigens was tested in clinical trials, which showed encouraging response to the vaccine formula (<xref ref-type="bibr" rid="B15">Campbell et&#xa0;al., 1996</xref>). It is worth remembering that immune responses elicited by an isolated antigen are not long-lasting (lack of immunological memory) and are not T cell-dependent, thus antigen conjugation to carrier protein could enhance its immunogenicity (<xref ref-type="bibr" rid="B76">Lin et&#xa0;al., 2022</xref>). <xref ref-type="bibr" rid="B76">Lin et&#xa0;al. (2022)</xref> developed a new method of obtaining conjugated vaccine antigens by using K1 and K2 CPS depolymerases to receive depolymerized CPS without losing their modifications (related to CPS immunogenicity), which typically appear after applying standard chemical reagents. Vaccination of mice with K1 and K2 oligosaccharides conjugated with CRM197 carrier protein induced anti-CPS antibodies and protected mice from subsequent infection by the respective <italic>K. pneumoniae</italic> K-serogroup (<xref ref-type="bibr" rid="B76">Lin et&#xa0;al., 2022</xref>). The last type of the above-mentioned vaccines is the epitope-driven formula. It would be ideal if such a vaccine included many epitopes common to antigens of different bacterial species. The fragments (marked with frames in <xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3</bold>
</xref>) common for <italic>K. pneumoniae</italic> CPS and <italic>P. mirabilis</italic> OPS may be potential candidates for the multi-epitope formula development. Importantly, some of the fragments also occur in OPS of other <italic>Enterobacterales</italic> LPSs (<xref ref-type="bibr" rid="B57">Knirel, 2011</xref>), which gives a chance to obtain a broad spectrum of immune system inducers. It should be remembered that the construction of a vaccine of that type requires applying complex modern methodology <italic>e.g.</italic> bioinformatics tools for searching databases, multi-epitopes synthesis, cloning and protein expression methods. A novel multiepitope candidate vaccine based on the epitopes of nine common <italic>E. coli</italic> protein antigens, which were conserved for the epitopes of <italic>K. pneumoniae</italic> and <italic>P. mirabilis</italic> antigens and were MHC I and MHC II inducers, provided a significant protection in the bladder and kidneys in the UTI mice model (<xref ref-type="bibr" rid="B89">Oloomi et&#xa0;al., 2020</xref>).</p>
<p>Apart from the studies on the multiepitope vaccine including epitopes/fragments shared by both <italic>K. pneumoniae</italic> and <italic>P. mirabilis</italic> antigens, other investigations also concerned developing a vaccine formula based on one kind of antigen e.g. <italic>Klebsiella</italic> spp. capsule polysaccharide (mentioned above) or MR/K or <italic>P. mirabilis</italic> MrpH or Pta (<xref ref-type="bibr" rid="B15">Campbell et&#xa0;al., 1996</xref>; <xref ref-type="bibr" rid="B70">Lavender et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B130">Wang et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B6">Armbruster et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B8">Assoni et&#xa0;al., 2021</xref>).</p>
<p>MR/K-HA (type-3) - mannose-resistant <italic>Klebsiella</italic>-like hemagglutinins (19.5-21.5 kDa) agglutinate tannin treated ox erythrocytes and mediate binding of bacteria to human endothelial and uroepithelial cells, tubular basement membranes and Bowman&#x2019;s capsules of the kidneys and urinary catheters (<xref ref-type="bibr" rid="B101">Podschun and Ullmann, 1998</xref>; <xref ref-type="bibr" rid="B23">Di Martino et&#xa0;al., 2003</xref>; <xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B109">S&#x119;kowska and Gospodarek, 2007</xref>; <xref ref-type="bibr" rid="B108">R&#xf3;&#x17c;alski et&#xa0;al., 2012</xref>). It has been showed that type 3 fimbrial shaft (MrkA) facilitates bacterial interactions and biofilm formation on abiotic surfaces including catheters, which may lead to CAUTIs development (<xref ref-type="bibr" rid="B134">Wu and Li, 2015</xref>; <xref ref-type="bibr" rid="B65">Langstraat et&#xa0;al., 2001</xref>; <xref ref-type="bibr" rid="B112">Schroll et&#xa0;al., 2010</xref>). MR/K-HA were first discovered in <italic>Klebsiella</italic> spp. strains and they are the main adhesive factors of <italic>K. pneumoniae</italic>, occurring more frequently in clinical than in sewage isolates (<xref ref-type="bibr" rid="B23">Di Martino et&#xa0;al., 2003</xref>; <xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>). Mice immunization with recombinant MrkA or purified type III fimbriae induced protection in a pneumonia model (<xref ref-type="bibr" rid="B70">Lavender et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B130">Wang et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B8">Assoni et&#xa0;al., 2021</xref>).</p>
<p>MR/P fimbriae - mannose resistant <italic>Proteus</italic> like fimbriae (agglutinating untreated erythrocytes in the presence of mannose) are the most important fimbriae for enhancing the formation of <italic>P. mirabilis</italic> initial biofilm, involved in the upper urinary tract colonization (especially the bladder), pyelonephritis development and showing autoaggregative properties (<xref ref-type="bibr" rid="B49">Jansen et&#xa0;al., 2004</xref>). Administration of the purified <italic>P. mirabilis</italic> HI4320 MR/P fimbriae to mice by different routes provided protection against reinfection with a homologous strain in 63% of animals in the case of intranasal or transurethral routes (<xref ref-type="bibr" rid="B72">Li et&#xa0;al., 2004</xref>; <xref ref-type="bibr" rid="B6">Armbruster et&#xa0;al., 2018</xref>). When purified recombinant MrpA (the main structural subunit of MR/P) was tested as a vaccine antigen in an ascending and a hematogenous model of UTI in mice, the subcutaneously immunized animals appeared to be protected against <italic>P. mirabilis</italic> UTI (<xref ref-type="bibr" rid="B97">Pellegrino et&#xa0;al., 2003</xref>).</p>
<p>
<italic>Proteus</italic> toxic agglutinin (Pta) is a surface associated calcium-dependent subtilisin-like alkaline serine protease. Pta exhibits bifunctional action by mediating the autoaggregation of bacterial cells or eliciting cytopathic effects on cultured kidney and bladder epithelial cells. Pta seems to be pathogen specific and its activity during infection is probably urease dependent. The passenger domain containing catalytic residues (Ser366, His147, Asp533) accounts for Pta cytotoxic activity (<xref ref-type="bibr" rid="B3">Alamuri and Mobley, 2008</xref>). Pta is a promising vaccine antigen - mice immunization with purified intact Pta or the passenger domain (Pta-&#x3b1;), each conjugated with cholera toxin (CT) protects significantly against <italic>P. mirabilis</italic> UTI, mainly in the upper urinary tract (<xref ref-type="bibr" rid="B2">Alamuri et&#xa0;al., 2009</xref>).</p>
</sec>
<sec id="s5">
<title>5 <italic>Klebsiella</italic> spp. and <italic>Proteus</italic> spp. LPSs in the serological studies</title>
<p>Structural similarities between polysaccharides of <italic>Klebsiella</italic> spp. and <italic>Proteus</italic> spp. strains were revealed in numerous cross reactions of <italic>Klebsiella</italic> LPSs with polyclonal rabbit sera specific to 11 <italic>Proteus</italic> spp. strains (<xref ref-type="bibr" rid="B93">Palusiak, 2015</xref>; <xref ref-type="bibr" rid="B94">Palusiak, 2021</xref>). Using the Western blotting technique allowed showing the reactions which mainly concerned the high-molecular-species containing LPS moieties with O-polysaccharide chains. The patterns typical for LPS low-molecular-mass-species corresponding to core-lipid A fractions were also noticed in the case of four <italic>Klebsiella</italic> LPSs and <italic>P. penneri</italic> 2 antiserum. Considering the fact that the LPS core regions of the representatives of both genera are very similar to each other, mainly in their inner parts, the cross reactions concerning this region should be more common (<xref ref-type="bibr" rid="B94">Palusiak, 2021</xref>). However, it ought to be remembered that the polysaccharide part of LPS may restrict an access to the core region and thus the reactions with core-specific-antibodies may not have been detected (<xref ref-type="bibr" rid="B92">Palusiak, 2013</xref>).</p>
<p>The reactions differed in their intensity depending on the used serum and they were noticed not only for the representatives of different <italic>Proteus</italic> O serogroups but also for different species of the genus <italic>e.g</italic>. <italic>P. mirabilis</italic>, <italic>P. vulgaris</italic> or <italic>P. penneri</italic>. This observation might be crucial for the future selection of vaccine antigens which should be characterized by having common fragments with as many LPSs as it is possible to induce the broad spectrum of protection. It should be remembered that LPS exhibits high toxicity which limits the possibilities of using this antigen in the vaccine formula (<xref ref-type="bibr" rid="B8">Assoni et&#xa0;al., 2021</xref>). However polysaccharides only induced T-cell-independent response, thus a conjugated vaccine would be more recommended as promoting strong, long lasting responses in all age groups of individuals (<xref ref-type="bibr" rid="B8">Assoni et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B76">Lin et&#xa0;al., 2022</xref>).</p>
<p>An important question which should be addressed is whether the cross-reactions appear in opposite systems <italic>e.g. Proteus</italic> LPSs and <italic>Klebsiella</italic> antisera and <italic>Klebsiella</italic> LPSs and <italic>Proteus</italic> antisera. In the mentioned studies such cross-reactions appeared in the case of four LPSs, <italic>P. penneri</italic> 19, 22 and 60 and <italic>K. oxytoca</italic> 0.062, which may indicate them as potential vaccine antigens. However, the research should be further completed with the data from detailed structural studies to show which O antigen fragments contribute to cross-reactions (<xref ref-type="bibr" rid="B94">Palusiak, 2021</xref>). So far, antigen O of <italic>Shigella sonnei</italic> has been successfully used in vaccines administered to humans in clinical studies (<xref ref-type="bibr" rid="B68">Launay et&#xa0;al., 2017</xref>). Long-termed catheterized patients and those prone to the recurrent UTIs of <italic>Klebsiella</italic> spp. and <italic>P. mirabilis</italic> etiology may be predestined to receive the LPS vaccine <italic>via</italic> the intranasal route providing the highest protection (<xref ref-type="bibr" rid="B6">Armbruster et&#xa0;al., 2018</xref>).</p>
<p>Summarizing, both <italic>K. pneumoniae</italic> and <italic>P. mirabilis</italic> are important etiological factors of nosocomial infections, especially those affecting the urinary tract, which may be infected by both pathogens simultaneously (<xref ref-type="bibr" rid="B134">Wu and Li, 2015</xref>; <xref ref-type="bibr" rid="B87">O&#x2019;Hara et&#xa0;al., 2000</xref>; <xref ref-type="bibr" rid="B13">Brisse et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B78">Macleod and Stickler, 2007</xref>; <xref ref-type="bibr" rid="B108">R&#xf3;&#x17c;alski et&#xa0;al., 2012</xref>). Such polymicrobial infections are often difficult to treat due to the development of biofilm, in which the cells of both species may cooperate in reaching the upper parts of the tract, and to frequent multidrug resistance of the bacteria (<xref ref-type="bibr" rid="B78">Macleod and Stickler, 2007</xref>; <xref ref-type="bibr" rid="B48">Jacobsen et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B20">Cuevas et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B27">Drzewiecka and Lewandowska, 2016</xref>). Thus, there is a need to acquire better knowledge on the virulence factors of both pathogens, especially those exhibiting common features. For instance, the examination of common fragments in highly immunogenic polysaccharides <italic>i.e. K. pneumoniae</italic> CPSs and <italic>P. mirabilis</italic> OPSs (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3</bold>
</xref>) and detection of various cross-reactions (<xref ref-type="bibr" rid="B93">Palusiak, 2015</xref>; <xref ref-type="bibr" rid="B94">Palusiak, 2021</xref>) are of high importance for the creation of a vaccine protecting against both pathogens.</p>
</sec>
<sec id="s6" sec-type="author-contributions">
<title>Author contributions</title>
<p>AP conceived and designed of the review and prepared the whole manuscript.</p>
</sec>
<sec id="s7" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s8" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
</body>
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<glossary>
<title>Glossary</title>
<table-wrap position="anchor">
<table frame="hsides">
<tbody>
<tr>
<td valign="top" align="left">3-OH-C<sub>14</sub>
</td>
<td valign="top" align="left">3-hydroxytetradecanoic acid</td>
</tr>
<tr>
<td valign="top" align="left">L-Ara<italic>p</italic>4N</td>
<td valign="top" align="left">4-amino-4-deoxy-L-arabinopyranose</td>
</tr>
<tr>
<td valign="top" align="left">AS</td>
<td valign="top" align="left">ankylosing spondylitis</td>
</tr>
<tr>
<td valign="top" align="left">ATCC</td>
<td valign="top" align="left">American Type Culture Collection</td>
</tr>
<tr>
<td valign="top" align="left">BSIs</td>
<td valign="top" align="left">bloodstream infections</td>
</tr>
<tr>
<td valign="top" align="left">CAP</td>
<td valign="top" align="left">community-acquired pneumonia</td>
</tr>
<tr>
<td valign="top" align="left">CA-PLA</td>
<td valign="top" align="left">community-acquired pyogenic liver abscess</td>
</tr>
<tr>
<td valign="top" align="left">CAUTI</td>
<td valign="top" align="left">catheter-associated UTIs</td>
</tr>
<tr>
<td valign="top" align="left">Cho<italic>P</italic>
</td>
<td valign="top" align="left">choline phosphate</td>
</tr>
<tr>
<td valign="top" align="left">ETC</td>
<td valign="top" align="left">extracellular toxic complex</td>
</tr>
<tr>
<td valign="top" align="left">Etn<italic>P</italic>
</td>
<td valign="top" align="left">ethanolamine phosphate</td>
</tr>
<tr>
<td valign="top" align="left">CPS</td>
<td valign="top" align="left">capsular polysaccharide</td>
</tr>
<tr>
<td valign="top" align="left">Fuc</td>
<td valign="top" align="left">fucose</td>
</tr>
<tr>
<td valign="top" align="left">D-Fuc3N</td>
<td valign="top" align="left">3-amino-3-deoxy-D-fucose</td>
</tr>
<tr>
<td valign="top" align="left">Gal<italic>p</italic>
</td>
<td valign="top" align="left">galactopyranose</td>
</tr>
<tr>
<td valign="top" align="left">Gal<italic>f</italic>
</td>
<td valign="top" align="left">galactofuranose</td>
</tr>
<tr>
<td valign="top" align="left">GalA</td>
<td valign="top" align="left">galacturonic acid</td>
</tr>
<tr>
<td valign="top" align="left">GalAN</td>
<td valign="top" align="left">GalA amidated by aliphatic polyamines</td>
</tr>
<tr>
<td valign="top" align="left">GalN</td>
<td valign="top" align="left">galactosamine</td>
</tr>
<tr>
<td valign="top" align="left">D-GalNAc</td>
<td valign="top" align="left">2-acetamido-2-deoxy-D-galactose</td>
</tr>
<tr>
<td valign="top" align="left">Gal<italic>o</italic>NAc</td>
<td valign="top" align="left">open-chain of GalNAc</td>
</tr>
<tr>
<td valign="top" align="left">Glc</td>
<td valign="top" align="left">glucose</td>
</tr>
<tr>
<td valign="top" align="left">GlcA</td>
<td valign="top" align="left">glucuronic acid</td>
</tr>
<tr>
<td valign="top" align="left">GlcN</td>
<td valign="top" align="left">glucosamine</td>
</tr>
<tr>
<td valign="top" align="left">D-GlcNAc</td>
<td valign="top" align="left">2-acetamido-2-deoxy-D-glucose</td>
</tr>
<tr>
<td valign="top" align="left">D-Gro-1-<italic>P</italic>
</td>
<td valign="top" align="left">D-glycerol 1-phosphate</td>
</tr>
<tr>
<td valign="top" align="left">HAPS</td>
<td valign="top" align="left">hospital-acquired pneumonia</td>
</tr>
<tr>
<td valign="top" align="left">LD-Hep</td>
<td valign="top" align="left">L-<italic>glycero</italic>-D-<italic>manno</italic>-heptose</td>
</tr>
<tr>
<td valign="top" align="left">DD-Hep</td>
<td valign="top" align="left">D-<italic>glycero</italic>-D-<italic>manno</italic>-heptose</td>
</tr>
<tr>
<td valign="top" align="left">hvKP</td>
<td valign="top" align="left">hypervirulent <italic>K. pneumonia</italic>
</td>
</tr>
<tr>
<td valign="top" align="left">Kdo</td>
<td valign="top" align="left">3-deoxy-D-<italic>manno</italic>-oct-2-ulosonic acid</td>
</tr>
<tr>
<td valign="top" align="left">LPS</td>
<td valign="top" align="left">lipopolysaccharide</td>
</tr>
<tr>
<td valign="top" align="left">LPB</td>
<td valign="top" align="left">LPS binding protein</td>
</tr>
<tr>
<td valign="top" align="left">L-Lys</td>
<td valign="top" align="left">L-lysine</td>
</tr>
<tr>
<td valign="top" align="left">Man</td>
<td valign="top" align="left">mannose</td>
</tr>
<tr>
<td valign="top" align="left">Me</td>
<td valign="top" align="left">methyl group</td>
</tr>
<tr>
<td valign="top" align="left">MR/K-HA</td>
<td valign="top" align="left">mannose-resistant <italic>Klebsiella</italic>-like hemagglutinin</td>
</tr>
<tr>
<td valign="top" align="left">MR/P</td>
<td valign="top" align="left">mannose resistant <italic>Proteus</italic> like fimbriae</td>
</tr>
<tr>
<td valign="top" align="left">
<italic>Pyr</italic>
</td>
<td valign="top" align="left">
<italic>pyruvic acid</italic>
</td>
<td valign="top" align="left">
</td>
</tr>
<tr>
<td valign="top" align="left">
<italic>R</italic>-3HOBu</td>
<td valign="top" align="left">(<italic>R</italic>)-3-hydroxybutanoic acid</td>
</tr>
<tr>
<td valign="top" align="left">
<italic>R</italic>-Cet-Etn<italic>P</italic>
</td>
<td valign="top" align="left">
<italic>N</italic>-[(<italic>R</italic>)-1-carboxyethyl]ethanolamine phosphate</td>
</tr>
<tr>
<td valign="top" align="left">RA</td>
<td valign="top" align="left">rheumatoid arthritis</td>
</tr>
<tr>
<td valign="top" align="left">Rha</td>
<td valign="top" align="left">ramnose</td>
</tr>
<tr>
<td valign="top" align="left">Rib<italic>f</italic>
</td>
<td valign="top" align="left">ribofuranose</td>
</tr>
<tr>
<td valign="top" align="left">
<italic>rmpA</italic>
</td>
<td valign="top" align="left">regulator of the mucoid phenotype</td>
</tr>
<tr>
<td valign="top" align="left">OPS</td>
<td valign="top" align="left">O-polysaccharide</td>
</tr>
<tr>
<td valign="top" align="left">OS</td>
<td valign="top" align="left">oligosaccharide</td>
</tr>
<tr>
<td valign="top" align="left">
<italic>P</italic>Etn</td>
<td valign="top" align="left">2-aminoethyl phosphate</td>
</tr>
<tr>
<td valign="top" align="left">Pta</td>
<td valign="top" align="left">
<italic>Proteus</italic> toxic agglutinin</td>
</tr>
<tr>
<td valign="top" align="left">L-Ser</td>
<td valign="top" align="left">L-serine</td>
</tr>
<tr>
<td valign="top" align="left">S</td>
<td valign="top" align="left">smooth</td>
</tr>
<tr>
<td valign="top" align="left">SR</td>
<td valign="top" align="left">semi-rough</td>
</tr>
<tr>
<td valign="top" align="left">Suc</td>
<td valign="top" align="left">succinic acid</td>
</tr>
<tr>
<td valign="top" align="left">Sug</td>
<td valign="top" align="left">4-deoxy-<italic>threo</italic>-hex-4-enopyranosyluronic acid group</td>
</tr>
<tr>
<td valign="top" align="left">UTIs</td>
<td valign="top" align="left">urinary tract infections</td>
</tr>
<tr>
<td valign="top" align="left">TLR</td>
<td valign="top" align="left">Toll-like receptor</td>
</tr>
<tr>
<td valign="top" align="left">T4SS</td>
<td valign="top" align="left">type IV secretion system</td>
</tr>
<tr>
<td valign="top" align="left">Qui4N</td>
<td valign="top" align="left">4-amino-4-deoxy-D-quinovose</td>
</tr>
</tbody>
</table>
</table-wrap>
</glossary>
</back>
</article>