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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.2022.995933</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>Subversion of host cell signaling: The arsenal of Rickettsial species</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Huang</surname>
<given-names>Dan</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1784556"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Luo</surname>
<given-names>Jingjing</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>OuYang</surname>
<given-names>Xuan</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1419522"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Song</surname>
<given-names>Lei</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/982636"/>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Department of Respiratory Medicine, Center of Pathogen Biology and Infectious Disease, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University</institution>, <addr-line>Changchun</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology</institution>, <addr-line>Beijing</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Hua Niu, Affiliated Hospital of Guilin Medical University, China</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Tian Luo, University of Texas Medical Branch at Galveston, United States; Yong Qi, Huadong Research Institute for Medicine and Biotechniques, China</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Xuan OuYang, <email xlink:href="mailto:ouyangxuan626@163.com">ouyangxuan626@163.com</email>; Lei Song, <email xlink:href="mailto:lsong@jlu.edu.cn">lsong@jlu.edu.cn</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>31</day>
<month>10</month>
<year>2022</year>
</pub-date>
<pub-date pub-type="collection">
<year>2022</year>
</pub-date>
<volume>12</volume>
<elocation-id>995933</elocation-id>
<history>
<date date-type="received">
<day>16</day>
<month>07</month>
<year>2022</year>
</date>
<date date-type="accepted">
<day>04</day>
<month>10</month>
<year>2022</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2022 Huang, Luo, OuYang and Song</copyright-statement>
<copyright-year>2022</copyright-year>
<copyright-holder>Huang, Luo, OuYang and Song</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>Rickettsia is a genus of nonmotile, Gram-negative, non-spore-forming, highly pleomorphic bacteria that cause severe epidemic rickettsioses. The spotted fever group and typhi group are major members of the genus Rickettsia. Rickettsial species from the two groups subvert diverse host cellular processes, including membrane dynamics, actin cytoskeleton dynamics, phosphoinositide metabolism, intracellular trafficking, and immune defense, to promote their host colonization and intercellular transmission through secreted effectors (virulence factors). However, lineage-specific rickettsiae have exploited divergent strategies to accomplish such challenging tasks and these elaborated strategies focus on distinct host cell processes. In the present review, we summarized current understandings of how different rickettsial species employ their effectors&#x2019; arsenal to affect host cellular processes in order to promote their own replication or to avoid destruction.</p>
</abstract>
<kwd-group>
<kwd>Type IV secretion system</kwd>
<kwd>effector</kwd>
<kwd>virulence</kwd>
<kwd>invasion</kwd>
<kwd>actin</kwd>
<kwd>phosphoinositide</kwd>
</kwd-group>
<contract-num rid="cn001">2019YFC1200602</contract-num>
<contract-sponsor id="cn001">National Key Research and Development Program of China<named-content content-type="fundref-id">10.13039/501100012166</named-content>
</contract-sponsor>
<counts>
<fig-count count="1"/>
<table-count count="1"/>
<equation-count count="0"/>
<ref-count count="111"/>
<page-count count="11"/>
<word-count count="6321"/>
</counts>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<title>Introduction</title>
<p>As Gram-negative and obligate intracellular micro-organisms, rickettsiae belong to the order Rickettsiales, Alphaproteobacteria (<xref ref-type="bibr" rid="B103">Walker and Ismail, 2008</xref>; <xref ref-type="bibr" rid="B14">Chan et&#xa0;al., 2010</xref>). Blood-feeding arthropods are intermediate vectors, and eventually, rickettsial pathogens are transmitted to humans by arthropods, resulting in mild to life-threatening diseases with symptoms as follows: fever, rash, headache, splenomegaly, and lymphadenopathy. Rickettsial infections have a long history, dating from antiquity, and have had a great influence on the history and evolution of humanity (<xref ref-type="bibr" rid="B71">Quintal, 1996</xref>). With the development of medicine and science, the definition and classification of rickettsial organisms are more reasoned and accurate when combined with clinical manifestation and molecular methods. These include the methods described in Bergey&#x2019;s Manual of Systematic Bacteriology, 16S rRNA gene sequencing (<xref ref-type="bibr" rid="B21">Fournier and Raoult, 2009</xref>), and whole genome sequencing (<xref ref-type="bibr" rid="B46">Leclerque, 2008</xref>). Species within the genus Rickettsia can be categorized into four groups as follows: ancestral group (AG), including <italic>R</italic>. <italic>canadensis</italic> and <italic>R</italic>. <italic>bellii</italic>, which are the most distantly related rickettsiae; typhi group (TG), including <italic>R</italic>. <italic>typhi</italic>, which is the causative agent of endemic typhus dependent on rat fleas as a vector, and <italic>R</italic>. <italic>prowazekii</italic>, which is the etiologic agent of epidemic typhus dependent on louse dissemination to humans; transitional group (TRG), including <italic>R</italic>. <italic>australis</italic>, which is the agent responsible for Queensland tick typhus, <italic>R</italic>. <italic>felis</italic>; and spotted fever group (SFG), such as <italic>R</italic>. <italic>rickettsii</italic>, the causing agent of Rocky Mountain spotted fever (RMSF), in America and <italic>R</italic>. <italic>conorii</italic>, the causing agent of Mediterranean spotted fever (MSF) in Europe (<xref ref-type="bibr" rid="B27">Gillespie et&#xa0;al., 2009a</xref>).</p>
<p>The obligate intracellular survival and proliferation of rickettsial species are significantly different from those of facultative intracellular bacteria such as <italic>Legionella pneumophila</italic>, <italic>Listeria monocytogenes</italic>, and <italic>Salmonella Typhimurium</italic>. The reductive evolution of rickettsial genomes leads to succinct genomes that are dependent on the host cell substrate for a wide range of biochemical reactions. Because the survival of rickettsial species without host cells is not possible with reductive genomes (<xref ref-type="bibr" rid="B108">Wood and Azad, 2000</xref>), they have evolved sophisticated mechanisms to export various virulence factors to survive in host cells. For example, some of the effectors are secreted on the surface of <italic>rickettsia</italic> spp. in order to adhere to and invade host cells. The others are translocated into nutrient-rich cytoplasm, subverting host signaling pathways, evading innate immune defense, and developing a beneficial replication niche (<xref ref-type="bibr" rid="B52">Martinez and Cossart, 2004</xref>).</p>
<p>The transmission of <italic>rickettsia</italic> spp. to humans is <italic>via</italic> the bite of blood-sucking vectors or inhalation of arthropod feces. <italic>Rickettsia</italic> spp. infect microvascular endothelial cells and immune cells, such as macrophages and monocytes, in the initiation stage. When multiple bacteria lyse host cells and spread <italic>via</italic> the lymphatic system, a series of clinical manifestations occurs (<xref ref-type="bibr" rid="B85">Sahni et&#xa0;al., 2019</xref>). <italic>Rickettsia</italic> spp. increases its infective efficiency by activating phagocytosis in non-phagocytic cells through secreted adhesins and the interaction with the host cell receptors, which greatly contribute to successful entry into the cytoplasm by stimulating cytoplasmic signaling cascades (<xref ref-type="bibr" rid="B52">Martinez and Cossart, 2004</xref>). Escape from the phagosome or endosome is another step for <italic>rickettsia</italic> spp. to overcome and translocated virulence factors play predominant roles in this process, exemplified by phospholipases (PLs) (<xref ref-type="bibr" rid="B75">Rahman et&#xa0;al., 2013</xref>) and PI (phosphoinositide) kinases (<xref ref-type="bibr" rid="B101">Voss et&#xa0;al., 2020</xref>). The polymerization of cytoskeletal actin and the rearrangement of the PM (plasma membrane) are demonstrated to be significant for bacterial invasion and transmission, which are hijacked by <italic>rickettsia</italic> spp. (<xref ref-type="bibr" rid="B95">Teysseire et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B14">Chan et&#xa0;al., 2010</xref>). Given the replicated lifestyle of intracellular bacteria, the manipulation of the innate immune signaling pathways, such as autophagy (<xref ref-type="bibr" rid="B42">Huang and Brumell, 2014</xref>; <xref ref-type="bibr" rid="B110">Xu et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B24">Fu et&#xa0;al., 2022c</xref>), nuclear factor-kappaB (NF-&#x3ba;B) signaling pathway (<xref ref-type="bibr" rid="B73">Radulovic et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B111">Zhang et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B23">Fu et&#xa0;al., 2022b</xref>), and caspase-11-GSDMD-IL-1&#x3b1; signaling axis (<xref ref-type="bibr" rid="B100">Voss et&#xa0;al., 2022</xref>), is also an essential step for bacterial infection. Multiple virulence factors are involved in these biological functions, some of which are highly conserved, and others are specific or variable across species, indicating that species-specific analysis is necessary. Besides, unlike the functional redundancy in the effectors of <italic>Legionella</italic> species (<xref ref-type="bibr" rid="B93">Song et&#xa0;al., 2021</xref>;  <xref ref-type="bibr" rid="B92">Song et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B25">Fu et&#xa0;al., 2022a</xref>), each effector is crucial for the adherence, invasion, and intracellular replication of rickettsiae. Hence, we reviewed multiple rickettsial effectors implicated in the invasion, escape, replication, and spreading of unique species of the genus Rickettsia and elucidated new insights on how these virulence factors attenuate the host&#x2019;s innate immune defense and orchestrate the permissive replication niche.</p>
</sec>
<sec id="s2">
<title>Effectors from <italic>Rickettsia</italic> spp. of SFG</title>
<sec id="s2_1">
<title>Effectors involved in bacterial adherence and invasion</title>
<p>
<italic>R</italic>. <italic>rickettsii</italic> and <italic>R</italic>. <italic>conorii</italic> are etiologic agents of RMSF and MSF, respectively. They are the most virulent infections spread to humans by infected ticks among all rickettsioses with the potential of fatality, especially in young people (<xref ref-type="bibr" rid="B72">Quintero Velez et&#xa0;al., 2019</xref>). Upon the tick bite, the bacterium is transmitted into a small-to-medium-sized blood vessel, leading to increased vesicular permeability and fluid leakage and eventually causing continuous skin and tissue damage, such as rash, skin necrosis, and gangrene (<xref ref-type="bibr" rid="B57">Muzumdar et&#xa0;al., 2019</xref>). <italic>Rickettsia</italic> spp. are highly evolutive organisms that deploy multiple surface proteins (<xref ref-type="bibr" rid="B33">Gong et&#xa0;al., 2014</xref>) for invading the vascular endothelial cells and establishing a replication niche within a nutrient-rich cytoplasm.</p>
<p>The surface proteins of bacteria indicate that they are in the first line of interaction with eukaryotic cell components. Extensive experimental evidence suggests that members of the Sca (surface cell antigen) family mediate interactions with host cell membranes during the initial phases of infection. The family of Sca proteins, namely Sca0 (OmpA), Sca1-4, Sca5 (OmpB), and other putative Sca 6-16 proteins (<xref ref-type="bibr" rid="B6">Blanc et&#xa0;al., 2005</xref>) are conserved and specific across <italic>rickettsia</italic> spp. Nevertheless, Sca1, Sca4, and Sca5 (OmpB) are highly conserved amongst all <italic>rickettsia</italic> spp.</p>
<p>Most Sca proteins, except Sca4, belong to the family of autotransporters (ATs) (also namely sec-dependent T5SS: type V secretion system), which have three modular domains, including an N-terminal (NT) signal sequence (SS), a central passenger domain, and a C-terminal translocation module (&#x3b2;-peptide) (<xref ref-type="bibr" rid="B14">Chan et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B30">Gillespie et&#xa0;al., 2015</xref>). The Sec translocon anchors in the bacterial inner membrane (IM) and is composed of the IM and cytosolic sections that act as a pathway to interact with Sca proteins through the NT helical transmembrane spanning (TMS) region and/or a strongly hydrophobic SS. The Sca proteins passage the Sec channel, then are secreted into the periplasm (PP) and complete the process from the IM to the PP. The NT SS is recognized and cleaved by signal peptidase (SPase) I. As a consequence, the C-terminal domain inserts into the outer membrane to form a &#x3b2;-barrel-rich transmembrane pore, which is responsible for transporting the passenger domain into the extracellular matrix (<xref ref-type="bibr" rid="B30">Gillespie et&#xa0;al., 2015</xref>). Collectively, the Sca proteins, the subset of rickettsial secreted proteins, are sec-dependent ATs localized on the surface of <italic>R</italic>. <italic>rickettsii</italic>, which contribute greatly to adherence and invasion into host cells.</p>
<p>
<italic>R</italic>. <italic>rickettsii</italic> possesses two major surface-exposed proteins of outer membrane protein A (OmpA molecular mass: 190 kDa) and outer membrane protein B (OmpB molecular mass: 120 kDa) (<xref ref-type="bibr" rid="B15">Dantas-Torres, 2007</xref>; <xref ref-type="bibr" rid="B63">Noriea et&#xa0;al., 2017</xref>). OmpB, also termed Sca5, is the most abundant protein in the outer membrane of <italic>R</italic>. <italic>rickettsii</italic>. The ectopic expression of the gene, OmpB, from the <italic>R</italic>. <italic>japonica</italic> genome in <italic>E</italic>. <italic>coli</italic> BL21 (DE3) is sufficient for bacterial adherence and invasion into Vero cells (<xref ref-type="bibr" rid="B97">Uchiyama et&#xa0;al., 2006</xref>). OmpB is the ligand of cell surface protein Ku70, which is a subunit of DNA-dependent protein kinase (DNA-PK), a serine/threonine kinase homologous to the PI3-kinase superfamily (<xref ref-type="bibr" rid="B53">Martinez et&#xa0;al., 2005</xref>). The interaction between OmpB and Ku70 is critical for the infection of non-phagocytic mammalian cells. The ubiquitin ligase of the host cell, c-Cbl, mediates the ubiquitination of Ku70 and contributes to <italic>R</italic>. <italic>conorii</italic> entry. The suppression of the endogenous expression of c-Cbl at the protein level reduces the <italic>R. conorii</italic>-induced ubiquitination of Ku70, which alleviates the invasion of <italic>R</italic>. <italic>conorii</italic> (<xref ref-type="bibr" rid="B13">Chan et&#xa0;al., 2009</xref>). Professor Martinez and his colleagues have further illustrated that OmpB-mediated infection culminates in actin recruitment at the bacterial foci, and actin polymerization is required in this entry process. A series of experimental results have also verified that clathrin and caveolin-dependent endocytic events likely contribute to the internalization process (<xref ref-type="bibr" rid="B13">Chan et&#xa0;al., 2009</xref>).</p>
<p>OmpA, also termed Sca0, mediates the adherence and invasion of <italic>R</italic>. <italic>conorii</italic>. The heterodimeric protein, &#x3b1;2&#x3b2;1 integrin, is a specific mammalian internalization receptor of OmpA, and blocking or decreasing the expression of &#x3b1;2&#x3b2;1 integrin markedly diminishes <italic>R</italic>. <italic>conorii</italic> invasion of endothelial cells (<xref ref-type="bibr" rid="B39">Hillman et&#xa0;al., 2013</xref>). Truncated OmpA and defects in the processing of OmpB are reasons why OmpA and OmpB are absent on the surface of avirulent strains (<xref ref-type="bibr" rid="B18">Ellison et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B63">Noriea et&#xa0;al., 2017</xref>). However, a single knockout of OmpA in the highly virulent Sheila Smith strain does not cause attenuation in a guinea pig model of the infection and entry into the endothelial cells (<xref ref-type="bibr" rid="B62">Noriea et&#xa0;al., 2015</xref>). These data further emphasize the critical role of OmpA and OmpB in bacterial entry into host cells.</p>
<p>Sca1 is highly conserved among SFG rickettsial species, including <italic>R</italic>. <italic>africae</italic>, <italic>R</italic>. <italic>rickettsii</italic> Sheila Smith, and <italic>R</italic>. <italic>japonica</italic> (<xref ref-type="bibr" rid="B59">Ngwamidiba et&#xa0;al., 2006</xref>). Ectopically expressed Sca1 in the <italic>E</italic>.&#xa0;<italic>coli</italic> system demonstrates that Sca1 is involved in <italic>R</italic>. <italic>conorii</italic> adherence to the host cells but not in the process of invasion (<xref ref-type="bibr" rid="B82">Riley et&#xa0;al., 2010</xref>). The presence of Sca2 in the <italic>R</italic>. <italic>conorii</italic> genome and the genome of virtually all SFG rickettsial species (<xref ref-type="bibr" rid="B59">Ngwamidiba et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B11">Cardwell and Martinez, 2009</xref>) suggests that Sca2 plays a critical role during the life cycle of rickettsiae. The expression of Sca2 at the outer membrane of <italic>E</italic>. <italic>coli</italic> is sufficient to mediate adherence to, and invasion of, various mammalian cells even in the absence of other rickettsial virulence factors. Furthermore, scanning and transmission electron micrographs show that the pretreatment of Vero cells with soluble Sca2 protein can reduce the invasion of <italic>R</italic>. <italic>conorii</italic> during infection (<xref ref-type="bibr" rid="B11">Cardwell and Martinez, 2009</xref>).</p>
<p>Besides, proteomic analysis using rickettsial species has identified that Sca family proteins contribute to bacterial entry into host cells, and there are two adhesions: Adr1 and Adr2 (<xref ref-type="bibr" rid="B79">Renesto et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B33">Gong et&#xa0;al., 2014</xref>). Adr1 and Adr2 are highly conserved across all rickettsial species, and their coding genes are <italic>RC1281</italic> and <italic>RC1282</italic> in the <italic>R</italic>. <italic>conorii</italic> genome, respectively. Sequestering by an anti-Adr2 monoclonal antibody reduces bacterial entry and rickettsiae-induced cytotoxicity (<xref ref-type="bibr" rid="B98">Vellaiswamy et&#xa0;al., 2011</xref>). However, the function of Adr1 is different from Adr2, which inhibits the complement system in order to help bacteria evade killing by innate and adaptive immune systems (<xref ref-type="bibr" rid="B83">Riley et&#xa0;al., 2014</xref>). It is well known that complement systems are responsible for killing and clearance of bacterial pathogens <italic>via</italic> large pore-forming complexes or the recruitment of immune cells (<xref ref-type="bibr" rid="B38">Heesterbeek et&#xa0;al., 2018</xref>). Although different bacteria interplay with different complement system regulators (<xref ref-type="bibr" rid="B91">Singh et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B36">Hallstrom et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B94">Syed and Wooten, 2021</xref>), the purpose is always to escape from complement-mediated killing. It is identified that a series of regulatory proteins, including factor I, factor H, C4-binding protein, vitronectin, and clusterin, regulate and block complement system activation. Adr1 of <italic>R</italic>. <italic>conorii</italic>, through double lysine amino acid residues located within loops 3 and 4 bound to the C terminal of vitronectin, realizes resistance to complement-mediated killing (<xref ref-type="bibr" rid="B83">Riley et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B20">Fish et&#xa0;al., 2017</xref>). Besides, some surface proteins (such as Sca5 and Adr2) are identified to be important protective antigens and have the potential ability to stimulate B cells to produce a specific antibody that recognizes <italic>R</italic>. <italic>rickettsii</italic>. INF-&#x3b3; and TNF-&#x3b1; levels are significantly elevated in mice immunized with a combination of Sca5 and Adr2 compared with the control group. Therefore, the surface proteins are potential candidates for subunit vaccines (<xref ref-type="bibr" rid="B32">Gong et&#xa0;al., 2015</xref>).</p>
</sec>
<sec id="s2_2">
<title>Effectors involved in subversion of host cells&#x2019; movement</title>
<p>In addition to the harnessing of Sca proteins and Adr1-2 to accomplish effective adherence to and invasion into host cells, diverse intracellular pathogens subvert the host actin polymerization machinery to drive movement within and between cells during infection (<xref ref-type="bibr" rid="B65">Pantaloni et&#xa0;al., 2001</xref>). The intracellular and intercellular mobility is responsible for infection from cytoplasmic bacteria to neighboring cells, which helps pathogens escape immune surveillance. Compared with most of the TGs, bacteria of the SFG have the capacity to move intracellularly and intercellularly (<xref ref-type="bibr" rid="B95">Teysseire et&#xa0;al., 1992</xref>), and other intracellular bacteria, such as <italic>Listeria</italic> and <italic>Shigella</italic>, have been demonstrated to manipulate the effectors ActA (<xref ref-type="bibr" rid="B106">Welch et&#xa0;al., 1998</xref>) and VirG/IcsA (<xref ref-type="bibr" rid="B54">Mauricio et&#xa0;al., 2017</xref>) to mimic or recruit host nucleation-promoting factors (NPFs).</p>
<p>The actin cytoskeleton is a dynamic filament network that is essential for cell movement, polarization, morphogenesis, and cell division. The assembly of actin filaments at the leading edge drives the movement of eukaryotic cells. Actin polymerization also contributes to providing force to internalize endocytic vesicles from the cell membrane (<xref ref-type="bibr" rid="B69">Pollard and Cooper, 2009</xref>). The members of the Rho family of small GTP-binding proteins, including Rac, Rho, and Cdc42, regulate actin-dependent processes (<xref ref-type="bibr" rid="B76">Rajat et&#xa0;al., 1999</xref>). WASP family proteins, especially WASP (Wiskott-Aldrich syndrome protein, which is only expressed in hematopoietic cells) and N-WASP (ubiquitously expressed, shared about 50% homology with WASP), mediate the effects of Cdc42 on the actin cytoskeleton. Active NPFs, such as N-WASp and Scar (<xref ref-type="bibr" rid="B51">Machesky et&#xa0;al., 1999</xref>), stimulate the nucleation activity of Arp2/3 (actin-related protein 2/3) complex through WCA domains which bind the Arp2/3 complex to initiate a new actin filament as a branch on an existing filament (<xref ref-type="bibr" rid="B19">Fassler et&#xa0;al., 2020</xref>). Because of sufficient ATP-actin-profilin, new branches extend rapidly, push the membrane forward, and form protrusions.</p>
<p>RickA, a 517-amino acid protein, is expressed on the surface of <italic>R</italic>. <italic>conorii</italic>. Actin polymerization assays <italic>in vitro</italic> show that RickA alone is unable to stimulate actin polymerization. However, it is efficient in accomplishing actin assembly when combined with the Arp2/3 complex (<xref ref-type="bibr" rid="B34">Gouin et&#xa0;al., 2004</xref>). The decrease in actin tails recruited by <italic>R</italic>. <italic>conorii</italic> in ScarWA-expressing cells is due to the overexpression of ScarWA sequestering Arp2/3, which further indicates that the Arp2/3 complex is hijacked during infection, as it is in <italic>Listeria</italic>-infected cells (<xref ref-type="bibr" rid="B8">Boujemaa-Paterski et&#xa0;al., 2001</xref>). Ectopic expression of RickA in Vero cells displays thin filopodia that are absent from non-transfected cells, reinforcing that RickA is a novel type of activator of actin nucleation through the activation of the Arp2/3 complex (<xref ref-type="bibr" rid="B34">Gouin et&#xa0;al., 2004</xref>). Western blotting analysis using a specific monoclonal antibody has shown that RickA is expressed in all tested SFG rickettsiae (including <italic>R</italic>. <italic>rickettsii</italic>, <italic>R</italic>.&#xa0;<italic>conorii</italic>, <italic>R</italic>. <italic>africae</italic>, <italic>R</italic>. <italic>sibirica</italic>, <italic>R</italic>. <italic>slovaca</italic>, etc.) but not in <italic>R</italic>.&#xa0;<italic>prowazekii</italic> and <italic>R</italic>. <italic>typhi</italic> (<xref ref-type="bibr" rid="B5">Balraj et&#xa0;al., 2008</xref>), which may be a partial reason why the TG bacteria do not exhibit actin-based motility. <italic>R</italic>. <italic>rickettsii</italic>-induced long actin-tail and actin-based motility are dependent on RickA, which activates both the nucleation and Y-branching activities of the Arp2/3 complex (<xref ref-type="bibr" rid="B43">Jeng et&#xa0;al., 2004</xref>). The universal existence of RickA and the similar function among SFG are coincident with the phenomenon of actin-based mobility (<xref ref-type="bibr" rid="B95">Teysseire et&#xa0;al., 1992</xref>), underlying the molecular mechanisms involved in cell-to-cell spread among the SFG.</p>
<p>Unlike the Arp2/3 complex, formin proteins, which are extensively present in all eukaryotes, produce unbranched actin filaments. The conserved formin homology (FH) domains, FH1 and FH2, are sufficient to <italic>de novo</italic> nucleate actin monomers to actin filament formation (<xref ref-type="bibr" rid="B10">Campellone and Welch, 2010</xref>). In <italic>R</italic>. <italic>parkeri</italic>, a representative SFG species, the Sca2 passenger domain contains a central cluster of three putative WH2 motifs flanked by two proline-rich domains (PRDs) that are similar to the FH1 domain of formins. The WH2 domain, especially the FH1 domain of Sca2, is highly conserved among SFG rickettsiae but absent from the TG, which is consistent with the lack of actin-based motility in the species. The Sca2 passenger domain mimics the function of formins and displays dose-dependent nucleation activity independently of host nucleators, eliminating the lag phase of polymerization. The intrinsic nucleation activity of Sca2 distinguishes it from RickA, which is dependent on the Arp2/3 complex (<xref ref-type="bibr" rid="B35">Haglund et&#xa0;al., 2010</xref>). In <italic>R. rickettsii</italic>, truncated Sca2, through transposon insertion, diminishes the unbranched actin comet tail induced by bacteria, leading to defective actin-based motility, while it does not affect the replication in Vero cells. Consequently, the Sca2 mutant <italic>R. rickettsii</italic> does not elicit the fever symptom in guinea pigs, which are used as a model system to assess rickettsial pathogenesis and display the small-plaque phenotype, showing that Sca2 is a crucial virulence determinant <italic>in vivo</italic> and <italic>in vitro</italic> (<xref ref-type="bibr" rid="B44">Kleba et&#xa0;al., 2010</xref>). Interestingly, <italic>R</italic>. <italic>peacockii</italic>, (members of SFG) which encodes an intact Sca2 and disrupts RickA, has a lack of actin-based motility (<xref ref-type="bibr" rid="B90">Simser et&#xa0;al., 2005</xref>). This observation indicates that at least these two key factors, Sca2 and RickA, coordinate with cell-to-cell spread. Taken together, these data suggest that Sca2 not only functions in the initial steps of rickettsial infection and the invasion of host cells (<xref ref-type="bibr" rid="B12">Cardwell and Martinez, 2012</xref>) but also drives bacterial intracellular and intercellular mobility, which effectively accelerates the cell-to-cell spread and evades the immune response.</p>
<p>Tension at the adjacent junction is considered a barrier in preventing cell-to-cell spread. Previous studies have justified that actin-driven motility is sufficient for bacterial spread (<xref ref-type="bibr" rid="B56">Monack and Theriot, 2001</xref>). <italic>R</italic>. <italic>parkeri</italic> employs distinct mechanisms compared with other pathogens. Sca4, previously named gene D, is an intracytoplasmic protein, and its matured molecular protein weight is 120 kDa. Moreover, Sca4 has a passenger domain similar to those of OmpA and OmpB but does not have a C-terminal AT domain (<xref ref-type="bibr" rid="B6">Blanc et&#xa0;al., 2005</xref>). Although it lacks the AT domain, Sca4 is secreted into the host cytoplasm dependent on C-terminal domains and is endowed with pivotal functions for cell-cell dissemination. The presence of two VBSs (vinculin binding sites) in Sca4 is necessary to bind the cell adhesion protein, vinculin, and it is demonstrated by the Co-IP assay that mutant Sca4 in the putative binding site (L415A, S416E, Y814I, and V820E) disrupts vinculin binding and decreases the number of protrusion engulfed formations (<xref ref-type="bibr" rid="B66">Park et&#xa0;al., 2011</xref>). Actually, this binding disrupts vinculin recruited by &#x3b1;-catenin, where it participates in actin-mediated reciprocal pulling forces to stabilize junctions (<xref ref-type="bibr" rid="B9">Buckley et&#xa0;al., 2014</xref>). This molecular mechanism underlies how <italic>R</italic>. <italic>parkeri</italic> relieves tension at the cell-to-cell junction and makes it easy to form protrusion engulfment, eventually promoting intracellular infection (<xref ref-type="bibr" rid="B45">Lamason et&#xa0;al., 2016</xref>).</p>
<p>Nowadays, a new discovery has been reported that roaM (regulator of actin-based motility) is increased by <italic>R</italic>. <italic>rickettsii</italic> to negatively modulate actin-based motility which is important for bacteria to propel themselves from the cytoplasm to adjacent cells. The study utilizes gene manipulation to deplete the ectopic expression of <italic>roaM</italic> gene in order to assess the role of roaM in actin-based motility. The data show that increased expression of roaM results in a dramatic reduction of actin comet tails, and depletion of this gene can rescue this phenotype. The <italic>roaM</italic> gene is intact in SFG <italic>Rickettsia</italic> spp., and it is not secreted into the host cell cytoplasm. Consequently, the mechanism of how the <italic>roaM</italic> gene regulates actin-based motility is independent of the activation of Arp2/3 or other NPFs (<xref ref-type="bibr" rid="B61">Nock et&#xa0;al., 2022</xref>). However, the expression of <italic>roaM</italic> also does not affect the expressions of Sca2, Sca4, and RickA, indicating that there are unknown effectors involved in actin-based motility.</p>
</sec>
<sec id="s2_3">
<title>Effectors involved in the escape from lysosome-mediated degradation</title>
<p>In the life cycle of rickettsiae, the initial step is to invade host cells through the Scas and Adr interactions with receptors on the surface of host cells, cascading the upstream signaling pathway to rearrange the cytoskeleton. The next challenge internalized bacteria are faced with is host lysosome-mediated degradation.</p>
<p>Bacteria evolved virulence factors to escape from the phagocytic vacuole into the cytoplasm and utilize the host energy substrate for plentiful multiplication. The pretreatment of <italic>R</italic>. <italic>rickettsii</italic> with PLA<sub>2</sub> (phospholipase A) inhibitors significantly decreases the percentage of infected Vero cells, the size of formative plagues (<xref ref-type="bibr" rid="B89">Silverman et&#xa0;al., 1992</xref>), and cell injury (<xref ref-type="bibr" rid="B102">Walker et&#xa0;al., 2001a</xref>). With the completion of the sequencing of <italic>R</italic>. <italic>conorii</italic>, the gene <italic>RC127</italic> has been reported to encode phospholipase D (PLD, molecular weight 24 kDa), which possesses a conserved H-K-D motif. The H-K-D motif is conserved in all members of the PLD superfamily and is critical for biochemical activity. The capacity of PLD is demonstrated by the release [<sup>3</sup>H]-choline from phosphatidyl [<sup>3</sup>H]-choline, which detects water-soluble radioactivity and comigrates with the choline standard through a thin layer chromatography assay. It is the consensus that phosphatidylcholine is the dominant constituent of cell membranes. A blockade of PLD by polyclonal antibody reduces the cytotoxicity of <italic>R</italic>. <italic>conorii</italic> and <italic>R</italic>. <italic>prowazekii</italic> when infecting Vero cells (<xref ref-type="bibr" rid="B78">Renesto et&#xa0;al., 2003</xref>). Pat1, which is conserved in sequenced rickettsial genomes, has G (glycine-rich motif), S (serine hydrolase motif), and D (active site aspartic acid) conserved catalytic sites. The mutants in S/D catalytic sites can disrupt the escape from phagosomal vacuoles into the host cell cytoplasm (<xref ref-type="bibr" rid="B75">Rahman et&#xa0;al., 2013</xref>).</p>
</sec>
<sec id="s2_4">
<title>Effectors involved in the disruption of immune surveillance</title>
<p>Besides elusion from lysosome-mediated degradation, rickettsial species also disrupt the biological function of the Golgi apparatus in host cells. Genomic comparisons between the virulent strain, <italic>R</italic>. <italic>rickettsii</italic> Sheila Smith, and the avirulent strain, Iowa, reveal that rickettsial ankyrin repeat protein 2 (RARP-2) in Iowa is truncated, and the deletion of 7 of 10 ankyrin repeat domains in the C terminal of the protein contributes to proteolytic degradation of the truncated RARP-2. The full-length protein is accurately colocalized with the endoplasmic reticulum (ER) (<xref ref-type="bibr" rid="B47">Lehman et&#xa0;al., 2018</xref>). Overexpression of the Sheila Smith RARP-2 in <italic>R</italic>. <italic>rickettsii</italic> Iowa converts this avirulent strain&#x2019;s typically nonlytic or opaque plaque type to a lytic plaque phenotype, which is similar to that of the virulent Sheila Smith strain. However, restoring the virulence of the Iowa strain in a guinea pig model is not observed, which is likely attributed to the multifactorial nature of rickettsial virulence (<xref ref-type="bibr" rid="B47">Lehman et&#xa0;al., 2018</xref>). RARP2 is a predicted cysteine protease related to eukaryotic caspases, and the mutant of a predicted active site cysteine to alanine (C109A) reverses the effect on the plaque phenotype. In the early stage of infection (4 hours after infection), fragmental trans-Golgi apparatus is induced by the&#xa0;<italic>R</italic>. <italic>rickettsii</italic> Sheila Smith strain at a very low load, while the phenotype is absent from the avirulent Iowa strain. The expression of RARP2 of <italic>R</italic>. <italic>rickettsii</italic> Sheila Smith in the avirulent Iowa strain causes dispersal of the <italic>trans</italic>-Golgi network, which is dependent on proteolytic activity and ankyrin repeat domains, indicating that colocalization with ER is significantly important for the function of RARP-2 (<xref ref-type="bibr" rid="B1">Aistleitner et&#xa0;al., 2020</xref>). Disrupting the <italic>trans</italic>-Golgi network leads to a defect in the glycosylation pattern of two cellular proteins: the <italic>trans</italic>-Golgi protein (TGN46) and MHC-I, meanwhile, the defect occurs in protein trafficking from the Golgi apparatus to the plasma membrane. MHC-I is an important antigen presentation protein that is a target of viruses and bacteria to hamper the cell delivery of antigens to immune cells and eventually evade immune surveillance (<xref ref-type="bibr" rid="B104">Walker et&#xa0;al., 2001b</xref>; <xref ref-type="bibr" rid="B2">Ambagala et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B3">Antoniou and Powis, 2008</xref>; <xref ref-type="bibr" rid="B86">Sahni et&#xa0;al., 2013</xref>). MHC-&#x406;-dependent antigen presentation is the initial step for adaptive immune responses. When the MHC-I gene is knocked out in the mouse model, the susceptibility of MHC-I KO mice is elevated 50,000 fold compared with wild-type C57BL/6 mice during SFG rickettsial infection (<xref ref-type="bibr" rid="B104">Walker et&#xa0;al., 2001b</xref>). An intracellular bacterium, <italic>Orientia tsutsugamushi</italic>, decreases the transcriptional level of MHC-I by reducing the cytosol level of NLRC5, the transactivator of MHC-&#x406;, in order to hamper biosynthesis of MHC-I (<xref ref-type="bibr" rid="B84">Rodino et&#xa0;al., 2019</xref>). Although the direct substrate of RARP-2 is unknown, ER location is a clue for discovering the substrate and has opportunities to elucidate that the inhibited delivery of MHC-I is either associated with the fragmental <italic>trans</italic>-Golgi or the RAPR-2 cleaved substrate. The secretion of PARP-2 is through Rvh T4SS (Rickettsiales vir homolog type IV secretion system, comprising VirB1-11 and T4SS coupling protein VirD4) (<xref ref-type="bibr" rid="B31">Gillespie et&#xa0;al., 2016</xref>), which is homologous with <italic>Agrobacterium tumefaciens</italic> virB/virD T4SS but devoid of VirB5 and VirB4. VirB6 and VirB8-9 are duplicated (<xref ref-type="bibr" rid="B28">Gillespie et&#xa0;al., 2009b</xref>; <xref ref-type="bibr" rid="B29">Gillespie et&#xa0;al., 2010</xref>). It is reported that the C terminus of T4SS substrates is recruited to RvhD4 (Rickettsia homology VirD4), which has the functions of substrate recognition and ATP hydrolysis (<xref ref-type="bibr" rid="B31">Gillespie et&#xa0;al., 2016</xref>), and the interaction is crucial for substrates to be transferred into the secretion machine (<xref ref-type="bibr" rid="B4">Atmakuri et&#xa0;al., 2003</xref>; <xref ref-type="bibr" rid="B99">Vergunst et&#xa0;al., 2005</xref>). However, experimental data are required to demonstrate whether the C terminus of PARP-2 is necessary to be transferred by T4SS.</p>
</sec>
</sec>
<sec id="s3">
<title>Effectors specific for <italic>Rickettsia</italic> spp. of TG</title>
<sec id="s3_1">
<title>Effectors involved in hemolysis and escape from phagocytic vacuoles</title>
<p>
<italic>R</italic>. <italic>typhi</italic> and <italic>R</italic>. <italic>prowazekii</italic> are major pathogenic species of the TG, which are the causative agents of endemic typhus and epidemic typhus, respectively. Despite the similarity in attachment, entry, and cytoplasmic proliferation, the members of the TG and SFG rickettsiae differ in several features. <italic>R</italic>. <italic>typhi</italic> and <italic>R</italic>. <italic>prowazekii</italic> adhere to and lyse erythrocytes, while the members of SFG rickettsiae are incapable of hemolysis. It is identified that the <italic>tlyC</italic> gene is specifically encoded by TG rickettsiae (<italic>R</italic>. <italic>typhi</italic> and <italic>R</italic>. <italic>prowazekii</italic>) but not SFG rickettsiae (<italic>R</italic>. <italic>rickettsii</italic>, <italic>R</italic>. <italic>australis</italic>, and <italic>R</italic>. <italic>akari</italic>), and transferring the <italic>tlyC</italic> gene into the non-hemolytic mutant <italic>P</italic>. <italic>mirabilis</italic> WPM111 (HpmA<sup>-</sup>) confers the mutant&#x2019;s hemolytic phenotype (<xref ref-type="bibr" rid="B74">Radulovic et&#xa0;al., 1999</xref>).</p>
<p>PLA2 is one of the most intensively studied membrane proteins, which hydrolyzes phospholipids at the sn-2 position to form fatty acids and lysophospholipid products (<xref ref-type="bibr" rid="B70">Quach et&#xa0;al., 2014</xref>). PLA2 binds to a membrane surface in a scooting mode and catalyzes the hydrolysis reaction of the sn-2 ester bond of phospholipids, which subsequently results in the destruction of the membrane surface. <italic>R</italic>. <italic>prowazekii</italic> encodes the RP534 protein, a homolog of the <italic>Pseudomonas aeruginosa</italic> ExoU, which is a secreted cytotoxin and has PLA activity (<xref ref-type="bibr" rid="B26">Gendrin et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B96">Tyson et&#xa0;al., 2015</xref>). The addition of bovine liver superoxide dismutase 1 (SOD1), an activator of ExoU, can shrink the duration to max value and increase the rate of RP534-mediated PC (phosphocholine) hydrolysis (<xref ref-type="bibr" rid="B40">Housley et&#xa0;al., 2011</xref>).</p>
<p>In <italic>R</italic>. <italic>typhi</italic>, <italic>RT0590</italic> and <italic>RT0522</italic> encode the Pat1 and Pat2 proteins, respectively. Pat1 homologs are encoded in all sequenced rickettsial genomes, and Pat2 is absent in SFG rickettsiae and highly conserved in TG rickettsiae, indicating a distinct life cycle within eukaryotic cells. The Pat2 homolog of <italic>R</italic>. <italic>prowazekii</italic> (<italic>RP534</italic>) also possesses PLA2 activity, which can be abolished through site-directed mutations in the catalytic Ser/Asp residues. Pat1 and Pat2 are secreted into the cytoplasm and are blocked by antibodies that can significantly decrease the numbers of plague formation and bacteria per cell and affect the escape from the phagocytic vacuole into cell cytosol (<xref ref-type="bibr" rid="B75">Rahman et&#xa0;al., 2013</xref>). In the comparison of activated time points of PLD, TlyA, TlyC, and Pat1 during the infection of rickettsia, reverse transcription PCR analyses found that <italic>tlyC</italic> and <italic>pld</italic> were transcribed during the period of phagosome escape, while <italic>tlyA</italic> and <italic>pat1</italic> were not. As we know, the strategies employed by <italic>Salmonella</italic> species in invading host cells are different from rickettsial species. Instead of escaping from phagosomal vacuoles, they adapt by replicating in phagosomal vacuoles and decorating them as SCV (<italic>Salmonella</italic>-containing vacuoles), which can not be recognized by lysosomes. The expression of TlyC or PLD endows <italic>Salmonella</italic> with the capacity to escape from phagosomal vacuoles into the cytoplasm, which further demonstrates the pivotal role of TlyC and PLD in the life cycle of <italic>R</italic>. <italic>prowazekii</italic> (<xref ref-type="bibr" rid="B107">Whitworth et&#xa0;al., 2005</xref>).</p>
<p>Members of TG rickettsiae employ abundant membranolytic effectors (TlyA, TlyC, Pld, Pat1, and Pat2) as a PL arsenal to lyse red blood cells and phagocytic vacuoles. The escaped bacteria rapidly replicate in the cytoplasm and accumulate plentiful numbers of offspring, depleting the mass nutrient substrate of host cells and eventually lysing cells for a new start of the life cycle (<xref ref-type="bibr" rid="B77">Ray et&#xa0;al., 2009</xref>). However, certain effectors involved in the process of lysis of the host cells remain elusive.</p>
</sec>
<sec id="s3_2">
<title>Effectors modulated phospholipid metabolism to promote bacterial invasion</title>
<p>Arfs (ADP ribosylation factors) are subfamilies of small GTP-binding proteins with low molecular weight and can bind to guanine nucleotides involved in vital intracellular processes, including signal transduction (<xref ref-type="bibr" rid="B49">Liu et&#xa0;al., 2017</xref>) and vesicle trafficking (<xref ref-type="bibr" rid="B48">Li and Guo, 2022</xref>). Arfs are classified into three types: type I (Arf1-3), type II (Arf4-5), and type III (Arf6). The type is dependent on the spatial distribution of the Arfs and a series of regulators (GEF: guanine nucleotide exchange factors, GAP: GTPase-activating proteins) to switch the Arfs from their GDP-bound inactivated form to a GTP-bound activated form (<xref ref-type="bibr" rid="B16">Donaldson and Jackson, 2011</xref>). Because of the significant function of Arf-GEF, bacterial pathogens mimic Arf-GEF to disturb the biological processes of the host cell (<xref ref-type="bibr" rid="B64">Orchard and Alto, 2012</xref>). The conserved Sec7 domain (<xref ref-type="bibr" rid="B109">Wright et&#xa0;al., 2014</xref>) helped scientists find that <italic>L</italic>. <italic>pneumophila</italic> and <italic>R</italic>. <italic>prowazekii</italic> encode the RaIF protein with a homology of the Sec7 domain. The RalF protein from <italic>L</italic>. <italic>pneumophila</italic>, a substrate of the Dot/Icm secretion system, is necessary for bacteria to hijack Arf1 localized on the surface of LCV (<italic>Legionella</italic>-containing vacuole) and subvert the host cell vesicle traffic from ER to LCV (<xref ref-type="bibr" rid="B58">Nagai et&#xa0;al., 2002</xref>).</p>
<p>However, the RaIF protein from <italic>R</italic>. <italic>typhi</italic> is distinguished from <italic>L</italic>. <italic>pneumophila</italic>, which interacts with RvhD4, a substrate of the type IV secretion system (<xref ref-type="bibr" rid="B80">Rennoll-Bankert et&#xa0;al., 2015</xref>). It colocalizes with Arf6 and PI5P4K (PIP4K) at the entry foci on the host PM. The accumulation of PI(4,5)P<sub>2</sub> by PIP4K is crucial for recruiting actin remodeling proteins, like Cdc42. Considering that the <italic>RaIF</italic> gene is pseudogenized or absent from SFG rickettsiae, it is a novel way for TG rickettsia to modulate host cell PI metabolism to benefit from bacterial invasion (<xref ref-type="bibr" rid="B81">Rennoll-Bankert et&#xa0;al., 2016</xref>).</p>
</sec>
<sec id="s3_3">
<title>Effectors modulated phospholipid metabolism to induce autophagy</title>
<p>Risk1 (<xref ref-type="bibr" rid="B101">Voss et&#xa0;al., 2020</xref>) is an effector with dual-class I and class III PI3K activities (<xref ref-type="bibr" rid="B22">Fox et&#xa0;al., 2020</xref>) secreted by rickettsia T4SS. Risk1 catalyzes PI(4,5)P<sub>2</sub> to PI(3,4,5)P<sub>3</sub> at the bacterial entry foci, contributing to <italic>R</italic>. <italic>typhi</italic> invading host cells at the primary stage. An antibody blockade of Risk1 on the surface of <italic>R</italic>. <italic>typhi</italic> significantly decreases the efficiency of bacterial entry into host cells. Risk1 depends on class III PI3K activity interacting with Beclin-1 and induces autophagy through simulating the function of class III PI3K activity (PtdIns3KC3, Vps34 in yeast) at the phagophore membrane nucleation step (<xref ref-type="bibr" rid="B42">Huang and Brumell, 2014</xref>). <italic>R</italic>. <italic>typhi</italic>-induced autophagy facilitates bacterial cytosol replication (<xref ref-type="bibr" rid="B101">Voss et&#xa0;al., 2020</xref>). There is extensive evidence that the PI signaling pathway is important in cell proliferation (<xref ref-type="bibr" rid="B88">Shaw and Cantley, 2006</xref>; <xref ref-type="bibr" rid="B87">Schink et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B37">Hasegawa et&#xa0;al., 2017</xref>), so the secretion of phospholipid kinases or phosphatases is also a universal tactic for bacteria to modulate the phospholipid metabolism of host cells. For example, <italic>L</italic>. <italic>pneumophila</italic> utilizes the MavQ-LepB_NTD (1&#x2013;311 amino acid in LepB)-SidF axis to generate PI4P on the surface of LCV (<xref ref-type="bibr" rid="B50">Luo and Isberg, 2004</xref>; <xref ref-type="bibr" rid="B17">Dong et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B41">Hsieh et&#xa0;al., 2021</xref>). PI4P is a marker of the Golgi organelle in the secretory pathway, and it anchors secreted effectors from Dot/Icm apparatus on LCV (<xref ref-type="bibr" rid="B105">Weber et&#xa0;al., 2006</xref>). <italic>Shigella flexneri</italic> exploits IpgD, a substrate of T3SS (type III secretion system) (<xref ref-type="bibr" rid="B68">Personnic et&#xa0;al., 2016</xref>), which is a phosphatase that catalyzes PI(4,5)P<sub>2</sub> to PI5P (<xref ref-type="bibr" rid="B60">Niebuhr et&#xa0;al., 2002</xref>) and up-regulates the PI3K-AKT signaling pathway (<xref ref-type="bibr" rid="B67">Pendaries et&#xa0;al., 2006</xref>) to inhibit apoptosis of infected cells. Accumulated PI5P also helps internalize ICAM-1, which is responsible for neutrophil recruitment to infected intestinal epithelial cells (<xref ref-type="bibr" rid="B7">Boal et&#xa0;al., 2016</xref>).</p>
</sec>
</sec>
<sec id="s4" sec-type="discussion">
<title>Discussion</title>
<p>The obligate intracellular life cycle of <italic>Rickettsia</italic> spp. includes entry into the host cells by phagocytosis (or induced phagocytosis for non-phagocytic cell types), rapid escape from phagocytic vacuoles into the host cytoplasm to evade phagosome-lysosome fusion, which promotes rickettsial survival and replication within the host cytoplasm, exit from the host cells by actin-mediated motility (SFG rickettsiae) or lysis of host cells (TG rickettsiae), and the evasion of complement-mediated killing into next infection stage (<xref ref-type="bibr" rid="B85">Sahni et&#xa0;al., 2019</xref>) (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>). In this review, we summarized the reported effectors of divergent rickettsial species from SFG and TG and focused on specific effectors (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>). The review elucidates that the SFG rickettsiae utilize RickA, Sca2, Sca4, and regulator <italic>roaM</italic> to manipulate actin-based intercellular transmission before infected cell lysis, which is significantly distinguished from the TG rickettsiae that spread to the uninfected cells after lysis of the infected cells (<xref ref-type="bibr" rid="B55">McGinn and Lamason, 2021</xref>). Well-developed PLs from the TG rickettsiae help bacterial hemolysis, and such a capacity is absent in the SFG rickettsiae. A modulated PI metabolism through T4SS effector Risk1 is a new discovery in TG rickettsiae. We hope to provide new insights through horizontal and vertical comparisons of the divergent effector proteins between SFG and TG. rickettsiae. However, most of the cited studies are exploratory rather than mechanistic, which is confounded by the problem of interaction between lineage-specific <italic>Rickettsia</italic> spp. and has often been studied without considering the complex host-microbial interaction environment that occurs <italic>in vivo</italic>. The characteristic of replicating and proliferating only within the cytoplasm or nucleus of the host cells poses a superior challenge for gene manipulation in rickettsiae (<xref ref-type="bibr" rid="B108">Wood and Azad, 2000</xref>). Therefore, the lack of effective gene manipulation systems for rickettsiae prevents us from obtaining direct evidence of the exact function of various genes at the different stages of infection.</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>The life cycle of TG <bold>(A)</bold> and SFG <bold>(B)</bold> rickettsiae. The effectors are exploited by <italic>rickettsial</italic> species from TG or SFG. <bold>(A)</bold> is the process of TG invasion of host cells by <italic>rickettsial</italic> species. Besides Adr1 subversion of complement-mediated killing in serum and a series of Scas and Adr2, bacteria from TG employed multiple PLs (Pat1/2, PLD, and TlyC), kinase (Risk1), and RaIF to disturb host cells PI metabolism. <bold>(B)</bold> is the process of SFG invasion of the host cells by <italic>rickettsial</italic> species. The significant characteristic of bacteria from SFG is the ability to spread before infected cell lysis, which utilizes a series of effectors (RickA, Sca2, and Sca4) to modulate cytoskeletal actin polymerization and PM rearrangement.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-12-995933-g001.tif"/>
</fig>
<table-wrap id="T1" position="float">
<label>Table&#xa0;1</label>
<caption>
<p>The virulence factors of rickettsial species.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="left">NO.</th>
<th valign="top" align="center">Effector</th>
<th valign="top" align="center">Representative Species</th>
<th valign="top" align="center">Gene ID</th>
<th valign="top" align="center">Function</th>
<th valign="top" align="center">Interactor/substrate</th>
<th valign="top" align="center">Reference</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">1</td>
<td valign="top" align="left">Sca5</td>
<td valign="top" align="center">
<italic>R. rickettsii</italic>
<break/>
<italic>R. conorii</italic> Malish7</td>
<td valign="top" align="center">
<italic>A1G_06030</italic>
<break/>
<italic>Rc1085</italic>
</td>
<td valign="top" align="center">Bacterial adherence and invasion</td>
<td valign="top" align="center">Ku70</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B53">Martinez et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B97">Uchiyama et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B13">Chan et&#xa0;al., 2009</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">2</td>
<td valign="top" align="left">Sca0</td>
<td valign="top" align="center">
<italic>R. rickettsii</italic>
<break/>
<italic>R. conorii Malish7</italic>
</td>
<td valign="top" align="center">
<italic>A1G_06990</italic>
<break/>
<italic>Rc1273</italic>
</td>
<td valign="top" align="center">Bacterial adherence and invasion</td>
<td valign="top" align="center">&#x3b1;2&#x3b2;1 integrin</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B39">Hillman et&#xa0;al., 2013</xref>);</td>
</tr>
<tr>
<td valign="top" align="left">3</td>
<td valign="top" align="left">Sca1</td>
<td valign="top" align="center">
<italic>R. japonica</italic>
</td>
<td valign="top" align="center">
<italic>RJP_0015</italic>
</td>
<td valign="top" align="center">Bacterial adherence</td>
<td valign="top" align="center">Unknown</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B59">Ngwamidiba et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B82">Riley et&#xa0;al., 2010</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">4</td>
<td valign="top" align="left">Sca2</td>
<td valign="top" align="center">
<italic>R. japonica</italic>
</td>
<td valign="top" align="center">
<italic>RJP_0085</italic>
</td>
<td valign="top" align="center">Bacterial adherence, invasion, and dissemination</td>
<td valign="top" align="center">G-actin</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B11">Cardwell and Martinez, 2009</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">5</td>
<td valign="top" align="left">Sca3</td>
<td valign="top" align="center">
<italic>R. typhi</italic>
</td>
<td valign="top" align="center">
<italic>RT0438</italic>
</td>
<td valign="top" align="center">Bacterial adherence and invasion</td>
<td valign="top" align="center">Unknown</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B30">Gillespie et&#xa0;al., 2015</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">6</td>
<td valign="top" align="left">Sca4</td>
<td valign="top" align="center">
<italic>R. parkeri</italic>
</td>
<td valign="top" align="center">
<italic>MC1_03740</italic>
</td>
<td valign="top" align="center">Relieves tension at the cell-to-cell junction</td>
<td valign="top" align="center">Vinculin</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B66">Park et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B45">Lamason et&#xa0;al., 2016</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">7</td>
<td valign="top" align="left">Adr1</td>
<td valign="top" align="center">
<italic>R. conorii</italic>
</td>
<td valign="top" align="center">
<italic>RC1281</italic>
</td>
<td valign="top" align="center">Evasion of host complement-mediate killing</td>
<td valign="top" align="center">Vitronectin</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B20">Fish et&#xa0;al., 2017</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">8</td>
<td valign="top" align="left">Adr2</td>
<td valign="top" align="center">
<italic>R. prowazekii</italic>
</td>
<td valign="top" align="center">
<italic>RP828</italic>
</td>
<td valign="top" align="center">Bacterial adherence and invasion</td>
<td valign="top" align="center">Unknown</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B98">Vellaiswamy et&#xa0;al., 2011</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">9</td>
<td valign="top" align="left">RickA</td>
<td valign="top" align="center">
<italic>R. rickettsii</italic>
</td>
<td valign="top" align="center">
<italic>RRR_04680</italic>
</td>
<td valign="top" align="center">Mimic WASPs activating Arp2/3 complex</td>
<td valign="top" align="center">Arp2/3 complex</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B34">Gouin et&#xa0;al., 2004</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">10</td>
<td valign="top" align="left">Pat1</td>
<td valign="top" align="center">
<italic>R. typhi</italic>
<break/>
<italic>R. prowazekii</italic>
</td>
<td valign="top" align="center">
<italic>RT0590</italic>
<break/>
<italic>RP602</italic>
</td>
<td valign="top" align="center">phospholipase A2 activity</td>
<td valign="top" align="center">PC (phosphocholine)</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B102">Walker et&#xa0;al., 2001a</xref>; <xref ref-type="bibr" rid="B75">Rahman et&#xa0;al., 2013</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">11</td>
<td valign="top" align="left">Pat2</td>
<td valign="top" align="center">
<italic>R. typhi</italic>
<break/>
<italic>R. prowazekii</italic>
</td>
<td valign="top" align="center">
<italic>RT0522</italic>
<break/>
<italic>RP534</italic>
</td>
<td valign="top" align="center">phospholipase A2 activity</td>
<td valign="top" align="center">PC (phosphocholine)</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B102">Walker et&#xa0;al., 2001a</xref>; <xref ref-type="bibr" rid="B75">Rahman et&#xa0;al., 2013</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">12</td>
<td valign="top" align="left">PLD</td>
<td valign="top" align="center">
<italic>R. conorii</italic>
</td>
<td valign="top" align="center">
<italic>Rc127</italic>
</td>
<td valign="top" align="center">phospholipase D activity</td>
<td valign="top" align="center">PC (phosphocholine)</td>    <td valign="top" align="center">(<xref ref-type="bibr" rid="B78">Renesto et&#xa0;al., 2003</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">13</td>
<td valign="top" align="left">tlyA</td>
<td valign="top" align="center">
<italic>R. prowazekii</italic>
</td>
<td valign="top" align="center">
<italic>RP555</italic>
</td>
<td valign="top" align="center">lysis erythrocytes</td>
<td valign="top" align="center">PC (phosphocholine)</td>
<td valign="top" rowspan="2" align="center">(<xref ref-type="bibr" rid="B74">Radulovic et&#xa0;al., 1999</xref>)<break/>(<xref ref-type="bibr" rid="B107">Whitworth et&#xa0;al., 2005</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">14</td>
<td valign="top" align="left">tlyC</td>
<td valign="top" align="center">
<italic>R. prowazekii</italic>
</td>
<td valign="top" align="center">
<italic>RP740</italic>
</td>
<td valign="top" align="center">lysis erythrocytes</td>
<td valign="top" align="center">PC (phosphocholine)</td>
</tr>
<tr>
<td valign="top" align="left">15</td>
<td valign="top" align="left">RARP-2</td>
<td valign="top" align="center">
<italic>R. rickettsii</italic>
</td>
<td valign="top" align="center">
<italic>A1G_05165</italic>
</td>
<td valign="top" align="center">Fragmentation of the <italic>trans</italic>-Golgi network</td>
<td valign="top" align="center">Unknown</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B47">Lehman et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B1">Aistleitner et&#xa0;al., 2020</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">16</td>
<td valign="top" align="left">RalF</td>
<td valign="top" align="center">
<italic>R. typhi</italic>
</td>
<td valign="top" align="center">
<italic>RT0362</italic>
</td>
<td valign="top" align="center">GEF of Arf6</td>
<td valign="top" align="center">Arf6</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B80">Rennoll-Bankert et&#xa0;al., 2015</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">17</td>
<td valign="top" align="left">Risk1</td>
<td valign="top" align="center">
<italic>R. typhi</italic>
</td>
<td valign="top" align="center">
<italic>RT0135</italic>
</td>
<td valign="top" align="center">class I and class III PI3Kinase</td>
<td valign="top" align="center">Rab5 and Beclin1</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B101">Voss et&#xa0;al., 2020</xref>)</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="s5" sec-type="author-contributions">
<title>Author contributions</title>
<p>DH drafted the original draft. JL edited the manuscript. XO and LS supervised and revised the manuscript. All authors contributed to the article and approved the submitted version.</p>
</sec>
<sec id="s6" sec-type="funding-information">
<title>Funding</title>
<p>This manuscript was funded by SKLPBS2132 (State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Science) and 2019YFC1200602 (National Key Research and Development Program of China).</p>
</sec>
<sec id="s7" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare 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>
<p>The reviewer YQ declared a past co-authorship with the author XO to the handling editor.</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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