Abstract
Viral infection had not been observed for amoebae, until the Acanthamoeba polyphaga mimivirus (APMV) was discovered in 2003. APMV belongs to the nucleocytoplasmatic large DNA virus (NCLDV) family and infects not only A. polyphaga, but also other professional phagocytes. Here, we review the Megavirales to give an overview of the current members of the Mimi- and Marseilleviridae families and their structural features during amoebal infection. We summarize the different steps of their infection cycle in A. polyphaga and Acanthamoeba castellani. Furthermore, we dive into the emerging field of virophages, which parasitize upon viral factories of the Megavirales family. The discovery of virophages in 2008 and research in recent years revealed an increasingly complex network of interactions between cell, giant virus, and virophage. Virophages seem to be highly abundant in the environment and occupy the same niches as the Mimiviridae and their hosts. Establishment of metagenomic and co-culture approaches rapidly increased the number of detected virophages over the recent years. Genetic interaction of cell and virophage might constitute a potent defense machinery against giant viruses and seems to be important for survival of the infected cell during mimivirus infections. Nonetheless, the molecular events during co-infection and the interactions of cell, giant virus, and virophage have not been elucidated, yet. However, the genetic interactions of these three, suggest an intricate, multilayered network during amoebal (co-)infections. Understanding these interactions could elucidate molecular events essential for proper viral factory activity and could implicate new ways of treating viruses that form viral factories.
Introduction to giant viruses
The discovery of giant viruses in the early 2000s led to a mind shift in the field of virology with respect to the potential origins of viruses (La Scola et al., 2003; Raoult et al., 2004). Originally, viruses were thought of as submicroscopic particles with a self-evident denial that viruses might exist, whose size would be large enough to be resolved with a simple light microscope (Lwoff, 1957; Raoult, 2013). Due to this mindset, the large, gram-positive particles in an Acanthamoeba polyphaga population were at first erroneously classified as bacteria (Birtles et al., 1997; La Scola et al., 2003; Raoult et al., 2007). Only the absence of ribosomal DNA in the presumed bacterium, led to the discovery and definition of the A. polyphaga mimivirus (APMV) in 2003 (La Scola et al., 2003). The acronym mimivirus (for mimicking microbe) reflects the resemblance to bacteria upon gram staining. At the same time, the discovery of APMV was the first ever report of a virus infecting amoebae. Amongst other features that are detailed below, APMV is unusual as it contains a large genome of 1.14 Mbp, thereby even surpassing the genome size of some bacterial species (Raoult et al., 2004). APMV particles are characterized by an up to 700 nm large capsid (Figure 1A), which is well above the resolution of a simple light microscope. Once it was established that giant DNA viruses of amoebae exist, many more such viruses, belonging to the nucleoplasmatic large DNA viruses (NCLDV) were found in the environment, as well as within a wide range of host organisms from humans, monkeys, and oysters (Boughalmi et al., 2013a; Dornas et al., 2014; Andrade et al., 2015). Ex vivo studies of human cell lines revealed that APMV is capable of infecting myeloid and mononuclear blood cells and interferes with the type I Interferon system (Silva et al., 2014). In addition, a distantly APMV-related NCLDV family member has been shown to productively infect T-lymphocytes under laboratory conditions (Popgeorgiev et al., 2013). In 2008, a small particle called Sputnik 1 (La Scola et al., 2008) was discovered in A. polyphaga, which parasitizes viral factories of giant viruses. Due to the functional similarity to bacteriophages in mediating lateral gene transfer, Sputnik was classified as a virophage (La Scola et al., 2008). Here, we will review the expanding family of virophages and discuss the implications for giant virus reproduction inside amoebae.
Figure 1
The diverse families of giant viruses that infect amoebae
The discovery of APMV sparked the interest in giant viruses and spawned a contemporary research field of its own (La Scola et al., 2003). Up until today, two giant virus families belonging to the NCLDV have been described that primarily infect amoebae: the Mimiviridae and the Marseilleviridae (Figure 1B). The latter has the A. polyphaga marseillevirus (APMaV) as founding member, which was discovered in 2009 (Boyer et al., 2009; Colson et al., 2013). In the last decade, nine additional viruses have been associated with the Marseilleviridae group (Colson et al., 2017). The Acanthamoeba castellani lausannevirus (ACLaV) was discovered by incubating water from the Seine river in France with A. castellani, a close relative of A. polyphaga (Thomas et al., 2011). ACLaV is the first known giant virus to encode histone-like proteins, which could point towards a DNA packaging mechanism similar to eukaryotes (Thomas et al., 2011). The Cannes 8 virus (Ca8V) (La Scola et al., 2010) and the Senegal virus (SNGV) (Lagier et al., 2012) have been isolated using similar co-culture methods and are grouped with the Marseilleviridae. The icosahedral capsid of the Marseilleviridae is between 190 and 250 nm in diameter (Colson et al., 2013). Like the genome of the Mimiviridae, the 370,000 bp dsDNA genome is encased in a lipid bilayer and encodes about 450 proteins (Boyer et al., 2009; La Scola et al., 2010; Thomas et al., 2011; Lagier et al., 2012). Both, Mimiviridae and Marseilleviridae, share only nine core genes with all NCLDVs (Figure 1C) and 180 genes are shared with at least two of the NCLDV families (Yutin et al., 2009; Yutin and Koonin, 2012). Based on the discovery of APMV and its complex genome, it was suggested to incorporate viruses into the tree of life by defining them as capsid-encoding organisms contrary to the ribosome-encoding organisms, which are represented by eukarya, bacteria, and archaea (Raoult and Forterre, 2008).
APMV—the best studied giant virus of amoebae
APMV was the first giant virus to be discovered (La Scola et al., 2008) and confronted the scientific community with features never observed in a virus before. Its capsid size and genetic complexity with many genes usually found in eukaryotic and prokaryotic cells challenged the Lwoff's characteristics of a virus (Raoult et al., 2004; Raoult and Forterre, 2008). The AT-rich 1.14 Mbp APMV genome features an impressive number of 979 protein-encoding genes in a dense arrangement (Raoult et al., 2004; Legendre et al., 2011). Several of its genes are only found in giant viruses of amoebae and code for virus-atypical proteins involved in DNA repair, protein folding, tRNA synthesis and translation, and more (Raoult et al., 2004). In addition, the APMV genome displays some plasticity and encodes self-splicing introns, inteins, and a specific set of mobile genetic elements called transpovirons (Desnues et al., 2012). Furthermore, the genome contains many genes likely acquired via horizontal gene transfer, paralogous genes, and so called ORFans, genes that encode proteins with unknown function (Suhre, 2005; Filée et al., 2007; Moreira and Brochier-Armanet, 2008; Forterre, 2010). Many of these genes are shared with the poxviruses, phycodnaviruses, and other NCLDVs (Filée et al., 2007). ORFans represent roughly 50% of genes and about 40% of the APMV proteome, which results in a high number of factors with unknown functions that might act during viral replication and morphogenesis (Renesto et al., 2006). Alike “classical” viruses, APMV genes are partly under the control of early and late stage-specific promoters (Raoult et al., 2004; Suhre et al., 2005).
The APMV particles possess remarkable structural features, separating them from the classical structures of viruses (Figure 1A). In its center, the viral DNA, mRNAs and proteins are packed into the core compartment (Xiao et al., 2009; Kuznetsov et al., 2013) and enclosed by a lipid membrane. Among the pre-packed proteins are 12 enzymes involved in transcription, five in DNA repair, two in RNA modification, and five in protein modification (Renesto et al., 2006). The central compartment is surrounded by an approximately 340 nm-large lipid bilayer and a secondary bilayer directly underneath an icosahedral capsid. This is comprised of major capsid proteins and features a five-branch proteinaceous structure, the “stargate,” at one vortex (Kuznetsov et al., 2013). The capsid itself is covered by a compact layer of about 120–140 nm long, heavily glycosylated fibrils, which potentially facilitate the attachment of APMV to its host cells (Rodrigues et al., 2015).
As of now, only four fiber associated proteins (FAP1-4) have been functionally associated with either fibril biosynthesis or as components of the fibrils (Sobhy et al., 2015). FAP1 is an aryl alcohol oxidase, which catalyzes the degradation of lignin or lignin derivatives. This suggests that APMV might also be able to infect lignin-containing algae (Klose et al., 2015; Rodrigues et al., 2015). However, the fibrils and associated proteins are not essential for the productive infection of amoebae: during long-term intraamoebal culture (150 generations), the responsible genes are lost (Boyer et al., 2011; Rodrigues et al., 2015). This indicates that the genomic complexity of APMV might be maintained to allow for a broad host range. If so, only a subset of its diverse molecular tools would come in use to enter and infect individual hosts.
Infection cycles of giant viruses in amoebae
Even though the replication cycle of most giant viruses differ in aspects like nuclear involvement, duration, assembly, and release of the viral progeny, key steps in the infection appear to be conserved, as summarized recently (Colson et al., 2017). For example, all known giant viruses enter the host cell by phagocytosis and release their DNA into the cytosol in a similar manner (Ghigo et al., 2008). Furthermore, viral replication takes place in specialized endoplasmatic reticulum (ER)-derived compartments that are found in the cytosol and are called viral factories (Xiao et al., 2009; Mutsafi et al., 2010; Kuznetsov et al., 2013).
After uptake, the virus resides in a de-novo phagosome. Subsequently, the phagosomal and viral membranes fuse, which allows the release of the viral core, that contains the genome, proteins, and mRNAs into the cytosol (Zauberman et al., 2008; Mutsafi et al., 2010). Alike the well-described poxvirus (Broyles, 2003), the structural integrity of the viral core seems to be retained until viral factories arise (Claverie et al., 2009; Mutsafi et al., 2010). Intriguingly, recent experiments suggest that viral transcription might be initiated already before the release of the viral core (Mutsafi et al., 2014). Once in the cytosol, replication of the viral genome begins immediately and the expression of early stage genes leads to the formation of early viral factories (Suzan-Monti et al., 2007; Mutsafi et al., 2013, 2014). The replication cycle is confined to the cytosol, again a trait shared with the poxvirus (La Scola et al., 2003; Claverie et al., 2009). This also suggests that giant viruses (like the poxvirus) must carry transcription complexes to initiate transcription immediately after infection (Resch et al., 2007; Claverie et al., 2009). In later stages of infection, these viral factories merge into one large cytosolic compartment for replication and capsid assembly (Suzan-Monti et al., 2007; Mutsafi et al., 2014). It should be noted that viral factories are not chaotic, but rather appear to feature distinct assembly lines for their progeny. The viral factory is made up of functional regions playing discrete roles in replication, capsid assembly, DNA packaging, and attachment of fibrils (Suzan-Monti et al., 2007; Mutsafi et al., 2014). In the outermost layer of the viral factory, the internal membrane layers of APMV are assembled from host-derived membrane vesicles, which are thought to rupture, thereby forming open single-layer membrane sheets (Mutsafi et al., 2013). Capsid assembly occurs around these membrane sheets and is scaffolded by the major capsid protein L425 (Mutsafi et al., 2013). Upon capsid formation, the genome is deposited into the empty viral particle through a transient interstice distal from the “stargate” structure (Zauberman et al., 2008). There is little evidence for a nuclear stage of giant viruses. However, the nuclei of A. polyphaga and A. castellani exhibit transient changes in their morphology during the early stages of infection with members of the Marseilleviridae family (Arantes et al., 2016). This indicates that nuclear host factors might play a role in the APMV replication, a notion that is supported by a two-fold decrease of the nuclear size in infected A. polyphaga cells (Colson et al., 2017). This might be due to a substantial redistribution of nuclear factors for viral replication, transcription or other processes (Colson et al., 2017). Albeit indirectly, this scenario is supported by data on the cytoplasmic replication of the Vaccinia virus (a poxvirus), to which mimivirus replication bears similarities (Mutsafi et al., 2010) and for which the involvement of nuclear enzymes has been demonstrated (Oh and Broyles, 2005).
Virophages as parasites of the megavirales
The description of Megavirales infection of amoebae was followed by the discovery of the fascinating virophage Sputnik in 2008 (La Scola et al., 2008). Sputnik was found infecting the viral factories of the mamavirus, a close relative of APMV (La Scola et al., 2008). Replication of the Sputnik virophages inside APMV-infected A. castellani cells is deleterious to APMV replication and results in abortive DNA replication and disruption of capsid biogenesis (La Scola et al., 2008). There is an ongoing discussion on the classification of virophages, that are denoted in several articles as satellite viruses (Krupovic and Cvirkaite-Krupovic, 2011; Blanc et al., 2015; Koonin and Krupovic, 2017). Satellite viruses are characterized by their dependency on factors of a helper virus. However, the Sputnik genomes itself encodes factors involved in viral replication (La Scola et al., 2008), suggesting that Sputnik can be classified as a virus, rather than a defective viral particle or sub-viral agent (Fischer, 2011; Desnues and Raoult, 2012).
All known members of the virophage family parasitizing on giant viruses are categorized into the large virus-dependent or -associated (Lavida-)viridae family that is divided into the Sputnikvirus and Mavirus genera (Krupovic et al., 2016). At the species level, the Sputnikvirus genus can be differentiated into the APMV-dependent Sputnik virophage and the APMV-dependent Zamilon virophage (Table 1), while Mavirus genus contains only the Cafeteria roenbergensis virus (CroV)-dependent mavirus (Krupovic et al., 2016).
Table 1
| Family | La | Name | Place discovered | Size [nm] | References | GenBank Acc. No. | Genome size [kbp] | No. of ORFs (predicted) | GC% | Virophage | References |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Mimiviridae | A | A. polyphaga mimivirus | Bradford, England | 750 | La Scola et al., 2003 | NC_014649.1 | 1,182 | 979 | 28 | Sputnik | La Scola et al., 2008 |
| A | A. polyphaga mamavirus | Paris, France | 750 | Colson et al., 2011 | JF801956.1 | 1,192 | 1023 | 28 | Sputnik | La Scola et al., 2008 | |
| A | Hirudovirus | Tunisia | 520 | Boughalmi et al., 2013a | KF493731.1 | 1,155 | 992 | 28 | No report | ||
| A | Niemeyer virus | Belo Horizonte, Brazil | 620 | Boratto et al., 2015 | KT599914.1 | 1,299 | 1003 | 28 | No report | ||
| A | Samba virus | Negro River, Brazil | 570 | Campos et al., 2014; Assis et al., 2015 | KF959826.2 | 1,181 | 971 | 28 | Rio Negro | Campos et al., 2014 | |
| A | Amazonian virus | Negro River, Brazil | Assis et al., 2015 | KM982403 | 1,180 | 979 | 27 | No report | |||
| A | Kroon virus | Lagoa Santa, Brazil | Assis et al., 2015 | KM982402.1 | 1,222 | 944 | 27 | No report | |||
| A | Oyster virus | Florianópolis, Brazil | Assis et al., 2015 | KM982401.1 | 1,200 | 948 | 27 | No report | |||
| A | Pointe-Rouge 1 virus | Marseille, France | 390 | La Scola et al., 2010 | LN871174.1 | 1,151 | Sputnik | Gaia et al., 2013 | |||
| A | Longchamps virus | 450 | La Scola et al., 2010 | LN871173.1 | 1,104 | Sputnik | Gaia et al., 2013 | ||||
| A | Fauteuil virus | 600 | La Scola et al., 2010 | LN871163.1 | 1,181 | Sputnik | Gaia et al., 2013 | ||||
| A | Terra2 virus | Marseille, France | 370 | La Scola et al., 2010; Yoosuf et al., 2014b | KF527228.1 | 1,167 | 890 | 28 | Sputnik | Gaia et al., 2013 | |
| A | Pointe-Rouge 2 virus | Marseille, France | 500 | La Scola et al., 2010 | LN871172.1 | 1,163 | Sputnik | Gaia et al., 2013 | |||
| A | Lactour virus | 450 | La Scola et al., 2010 | CXOL00000000.1* | 1,181 | Sputnik | Gaia et al., 2013 | ||||
| A | Lentille virus | Marseille, France | 500 | La Scola et al., 2010 | AFYC00000000.1* | 1,193 | 807 | Sputnik | La Scola et al., 2010 | ||
| A | Shirakomae virus | Nagano, Japan | Takemura et al., 2016 | AP017645.1 | 1,183 | 996 | No report | ||||
| A | Kasaii virus | Tokyo, Japan | Takemura et al., 2016 | AP017644.1 | 1,183 | 996 | No report | ||||
| A | Bombay virus | Mumbai, India | 435 | Chatterjee et al., 2016b | KU761889.1 | 1,182 | 898 | 28 | No report | ||
| B | A. polyphaga moumouvirus | South-East France | 420 | La Scola et al., 2010; Yoosuf et al., 2012 | NC020104.1 | 1,021 | 930 | Sputnik | Gaia et al., 2013 | ||
| B | Monve virus | 390 | La Scola et al., 2010 | JN885994-6001* | 1,015 | Sputnik | Gaia et al., 2013 | ||||
| B | Saudi moumouvirus | Jeddah, Saudi Arabia | 500 | Bajrai et al., 2016 | KY110734.1 | 1,046 | 868 | 26 | No report | ||
| B | Goulette virus | Boughalmi et al., 2013c | KC008572.1 | 1,017 | 979 | No report | |||||
| C | Megavirus chiliensis | Las Cruces, Chile | 700 | Arslan et al., 2011 | JN258408.1 | 1,259 | 1120 | 25 | No report | ||
| C | LBA111 virus | Tunisia | 550 | Saadi et al., 2013a | JX885207.1 | 1,231 | 1183 | No report | |||
| C | Courdo 11 virus | Saint-Raphael, France | 450 | La Scola et al., 2010; Yoosuf et al., 2014a | JX975216.1 | 1,246 | 1166 | Sputnik | Gaia et al., 2013 | ||
| C | Courdo 7 virus | France | 400 | La Scola et al., 2010 | JN885990-3 | 1,000 | Sputnik | Gaia et al., 2013 | |||
| C | Terra1 virus | Marseille, France | 420 | La Scola et al., 2010; Yoosuf et al., 2014b | KF527229.1 | 1,234 | 1055 | 25 | Sputnik | Gaia et al., 2013 | |
| C | Shan virus | Marseille, France | 640 | Saadi et al., 2013b | LN868520.1 | 1,259 | No report | ||||
| C | Courdo5 virus | 400 | La Scola et al., 2010 | LN868540.1 | 0,922 | Sputnik | Gaia et al., 2013 | ||||
| C | Powai Lake megavirus | Mumbai, India | 425 | Chatterjee et al., 2016a | KU877344.1 | 1,209 | 996 | 25 | No report | ||
| C | Bus virus | 400 | La Scola et al., 2010 | LN868539.1 | 1,229 | Sputnik | Gaia et al., 2013 | ||||
| C | Avenue 9 virus | Boughalmi et al., 2013c | LN867403.1 | 1,214 | No report | ||||||
| C | Montpellier 3 virus | Montpellier, France | 370 | La Scola et al., 2010 | LN868518.1 | 1,243 | Sputnik | Gaia et al., 2013 | |||
| C | Mont1 virus | Tunisia | 500 | Boughalmi et al., 2013c | Zamilon | Gaia et al., 2014 | |||||
| Marseilleiviridae | A | Marseillevirus marseillevirus T19 | Paris, France | 250 | Boyer et al., 2009 | NC_013756 | 0,368 | 457 | 45 | No report | |
| A | Giant blood marseillevirus | Marseille, France | 220 | Popgeorgiev et al., 2013 | PRJNA185405* | 0,357 | 617 | 45 | No report | ||
| A | Cannes8 virus | Cannes, France | 190 | La Scola et al., 2010; Aherfi et al., 2013 | KF261120 | 0,374 | 484 | No report | |||
| A | Senegalvirus | N'diop, Senegal | 200 | Lagier et al., 2012 | JF909596-602* | 0,373 | No report | ||||
| A | Melbournevirus | Melbourne, Australia | 200 | Doutre et al., 2014 | KM275475.1 | 0,369 | 403 | 45 | No report | ||
| B | Lausannevirus | Seine River, France | 200 | Thomas et al., 2011 | NC_015326 | 0,347 | 450 | No report | |||
| B | Port-Miou virus | Port-Miou Calanque, France | 200 | Doutre et al., 2015 | KT428292.1 | 0,349 | 410 | No report | |||
| B | Noumeavirus | Noumea, New Caledonia | 200 | Fabre et al., 2017 | NC_033775 | 0,376 | 452 | 43 | No report | ||
| C | Tunisvirus | Tunis, Tunisia | 250 | Boughalmi et al., 2013c; Aherfi et al., 2014 | KF483846.1 | 0,380 | 484 | 43 | No report | ||
| C | Insectomime virus | Tunis, Tunisia | 225 | Boughalmi et al., 2013b | KF527888.1 | 0,387 | 477 | 43 | No report | ||
| C | Tokyovirus A1 | Arakawa River, Japan | 200 | Takemura, 2016 | AP017398.1 | 0,373 | 487 | No report | |||
| D | Brazilian marseillevirus | Belo Horizonte, Brazil | 250 | Dornas et al., 2015, 2016 | NC_029692 | 0,362 | 491 | 43 | No report | ||
| E | Golden marseillevirus | Guaíba Lake, Brazil | 200 | Dos Santos et al., 2016 | KT835053.1 | 0,361 | 483 | 43 | No report |
Overview of the Mimiviridae and Marseilleviridae families and experimentally shown virophage infections.
Genomes with separate available contigs or only raw sequencing data.
Lineage.
Virophage replication has been extensively studied in particular for Sputnik, Zamilon and mavirus. Studies on amoebae infected with different mimiviruses revealed that Sputnik virophages can parasitize mimiviruses from all Mimiviridae lineages but apparently not the Marseilleviridae lineages (Gaia et al., 2013). Sputnik replicates inside mamavirus-infected A. castellani cells within the viral factories, nonetheless, with different kinetics as the mamavirus and at multiple hot spots inside the factory (La Scola et al., 2008). In APMVs viral factories, Sputnik infection results in the emergence of newly generated particles 6 h post infection with a concomitant decrease of infective APMV particles (Ogata and Claverie, 2008). The 18,343-kilobase circular dsDNA genome of Sputnik possesses 21 partly overlapping open-reading frames (ORFs) encoding for several factors involved in DNA replication (La Scola et al., 2008). Interestingly, four of the ORFs are strongly homologous to APMV-encoded genes (La Scola et al., 2008; Gaia et al., 2013). Since Sputnik virophages encodes a lambda-type integrase, the molecular tools for genomic integration are present (La Scola et al., 2008). Indeed, an integration of the Sputnik genome into the genome of the Lentille virus, a relative of APMV, could be observed experimentally (Desnues et al., 2012). There is no indication of Sputnik genome integration into the host cell genome, in line with the lack of indications for a nuclear phase.
The Zamilon virophage (belonging to the Sputnikvirus genus) was discovered together with the Mont1 mimivirus in soil samples from Tunisia (Boughalmi et al., 2013a; Gaia et al., 2014). The 60 nm-wide, spherical virophage carries a 17,276 bp dsDNA genome encoding 20 genes. Although Zamilon shares 76% of its genomic sequence with Sputnik, Zamilon can only infect lineages B and C (Gaia et al., 2014). Furthermore, the tv_L8 protein, encoded in the transpovirons of the Monve mimivirus, shares significant homology with the ORF8-encoded protein of Zamilon (Gaia et al., 2014). This suggests that an exchange of genetic material can in principle occur between the giant virus and the Zamilon virophage within co-infected amoebae, although this has not been observed experimentally so far.
The Maverick-related virus (mavirus), lonely member of the Mavirus genus, parasitizes the viral factories of CroV that infects the marine heterotrophic nanoflagellate C. roenbergensis (Fischer et al., 2010; Fischer and Suttle, 2011). Although this review is predominantly concerned with infection of amoebae, mavirus is included here for its unique features for a virophage. Its 19,063 bp circular genome possesses 20 ORFs including a retroviral integrase, an unsual, protein-primed DNA polymerase, plus four additional proteins, all of which are also found conserved in Maverick/Polinton (MP) retroelements (Fischer and Suttle, 2011; Krupovic et al., 2014, 2016). Additionally, the termini of the mavirus genome consist of long terminal repeats similar to those found in MP retroelements (Yutin et al., 2013; Krupovic et al., 2016). Both findings suggest that these retroelements might have originated from mavirus genome integration events in mavirus co-infected cells (Fischer and Suttle, 2011; Krupovic et al., 2016). Nonetheless, this hypothesis for the origins of MP retroelements remains to be tested experimentally. Fischer and Hackl (2016) succeeded to monitor the integration of mavirus into the C. roenbergensis genome by co-infection with a low multiplicity of infection of CroV. Intriguingly, genes in the mavirus genome possess promoter sequences similar to the late stage promoter of CroV (Fischer and Hackl, 2016). As a consequence, re-infection of C. roenbergensis carrying the integrated mavirus genome with CroV resulted in inhibition of CroV DNA replication, concomitantly with an increased survival of C. roenbergensis (Fischer and Hackl, 2016).
Other virophages have been discovered by metagenomic analysis of water samples [e.g., the Organic Lake virophage (Yau et al., 2011), the Yellowstone Lake virophages (Zhou et al., 2013, 2015)]. However, the viral and cellular host for these remain to be determined (Krupovic et al., 2016), unlike the situation of the Rio Negro virophage that has the Samba virus as viral host (Campos et al., 2014).
Outlook
Since the discovery of its first member APMV in 2003, new giant viruses are discovered continuously in samples from all over the world and added to the Megavirales family. The addition of virophages as parasites of giant viruses, their high abundance in the environment, and the genetic interactions between cell, giant virus, and virophage, suggest an intricate, multilayered network during amoebal co- and super-infections. Future studies of these dynamic interactions could elucidate the inner mechanics of viral factories.
Statements
Author contributions
All authors designed the mini review. JD: generated the figures and drafted the text; MH and CH: wrote the manuscript.
Funding
This work is supported by a grant of the Tönjes-Vagt-Stiftung Bremen, Germany.
Conflict of interest
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.
References
1
AherfiS.BoughalmiM.PagnierI.FournousG.La ScolaB.RaoultD.et al. (2014). Complete genome sequence of Tunisvirus, a new member of the proposed family Marseilleviridae. Arch. Virol.159, 2349–2358. 10.1007/s00705-014-2023-5
2
AherfiS.PagnierI.FournousG.RaoultD.La ScolaB.ColsonP. (2013). Complete genome sequence of Cannes 8 virus, a new member of the proposed family “Marseilleviridae.”Virus Genes47, 550–555. 10.1007/s11262-013-0965-4
3
AndradeK. R.BorattoP. P. V. M.RodriguesF. P.SilvaL. C. F.DornasF. P.PilottoM. R.et al. (2015). Oysters as hot spots for mimivirus isolation. Arch. Virol.160, 477–482. 10.1007/s00705-014-2257-2
4
ArantesT. S.RodriguesR. A. L.Dos Santos SilvaL. K.OliveiraG. P.SouzaH. L. D.KhalilJ. Y.et al. (2016). The large Marseillevirus explores different entry pathways by forming giant infectious vesicles. J. Virol.90, 5246–5255. 10.1128/JVI.00177-16
5
ArslanD.LegendreM.SeltzerV.AbergelC.ClaverieJ.-M. (2011). Distant Mimivirus relative with a larger genome highlights the fundamental features of Megaviridae. Proc. Natl. Acad. Sci. U.S.A.108, 17486–17491. 10.1073/pnas.1110889108
6
AssisF. L.BajraiL.AbrahaoJ. S.KroonE. G.DornasF. P.AndradeK. R.et al. (2015). Pan-genome analysis of Brazilian lineage A amoebal mimiviruses. Viruses7, 3483–3499. 10.3390/v7072782
7
BajraiL. H.de AssisF. L.AzharE. I.JardotP.RobertC.AbrahãoJ.et al. (2016). Saudi Moumouvirus, the first group B mimivirus isolated from Asia. Front. Microbiol.7:2029. 10.3389/fmicb.2016.02029
8
BirtlesR. J.RowbothamT. J.StoreyC.MarrieT. J.RaoultD. (1997). Chlamydia-like obligate parasite of free-living amoebae. Lancet349, 925–926. 10.1016/S0140-6736(05)62701-8
9
BlancG.Gallot-LavalléeL.MaumusF. (2015). Provirophages in the Bigelowiella genome bear testimony to past encounters with giant viruses. Proc. Natl. Acad. Sci. U.S.A.112, E5318–E5326. 10.1073/pnas.1506469112
10
BorattoP. V.ArantesT. S.SilvaL. C. F.AssisF. L.KroonE. G.La ScolaB.et al. (2015). Niemeyer virus: a new mimivirus group A isolate harboring a set of duplicated aminoacyl-tRNA synthetase genes. Front. Microbiol.6:1256. 10.3389/fmicb.2015.01256
11
BoughalmiM.PagnierI.AherfiS.ColsonP.RaoultD.La ScolaB. (2013a). First isolation of a giant virus from wild Hirudo medicinalis leech: Mimiviridae isolation in Hirudo medicinalis. Viruses5, 2920–2930. 10.3390/v5122920
12
BoughalmiM.PagnierI.AherfiS.ColsonP.RaoultD.La ScolaB. (2013b). First isolation of a Marseillevirus in the Diptera Syrphidae Eristalis tenax. Intervirology56, 386–394. 10.1159/000354560
13
BoughalmiM.SaadiH.PagnierI.ColsonP.FournousG.RaoultD.et al. (2013c). High-throughput isolation of giant viruses of the Mimiviridae and Marseilleviridae families in the Tunisian environment. Environ. Microbiol.15, 2000–2007. 10.1111/1462-2920.12068
14
BoyerM.AzzaS.BarrassiL.KloseT.CampocassoA.PagnierI.et al. (2011). Mimivirus shows dramatic genome reduction after intraamoebal culture. Proc. Natl. Acad. Sci. U.S.A.108, 10296–10301. 10.1073/pnas.1101118108
15
BoyerM.YutinN.PagnierI.BarrassiL.FournousG.EspinosaL.et al. (2009). Giant Marseillevirus highlights the role of amoebae as a melting pot in emergence of chimeric microorganisms. Proc. Natl. Acad. Sci. U.S.A.106, 21848–21853. 10.1073/pnas.0911354106
16
BroylesS. S. (2003). Vaccinia virus transcription. J. Gen. Virol.84, 2293–2303. 10.1099/vir.0.18942-0
17
CamposR. K.BorattoP. V.AssisF. L.AguiarE. R. G. R.SilvaL. C. F.AlbarnazJ. D.et al. (2014). Samba virus: a novel mimivirus from a giant rain forest, the Brazilian Amazon. Virol. J.11:95. 10.1186/1743-422X-11-95
18
ChatterjeeA.AliF.BangeD.KondabagilK. (2016a). Complete genome sequence of a new megavirus family member isolated from an Inland Water Lake for the First Time in India. Genome Announc.4:e00402-16. 10.1128/genomeA.00402-16
19
ChatterjeeA.AliF.BangeD.KondabagilK. (2016b). Isolation and complete genome sequencing of Mimivirus bombay, a Giant Virus in sewage of Mumbai, India. Genomics Data9, 1–3. 10.1016/j.gdata.2016.05.013
20
ClaverieJ.-M.GrzelaR.LartigueA.BernadacA.NitscheS.VaceletJ.et al. (2009). Mimivirus and Mimiviridae: giant viruses with an increasing number of potential hosts, including corals and sponges. J. Invertebr. Pathol.101, 172–180. 10.1016/j.jip.2009.03.011
21
ColsonP.La ScolaB.LevasseurA.Caetano-AnollésG.RaoultD. (2017). Mimivirus: leading the way in the discovery of giant viruses of amoebae. Nat. Rev. Microbiol.15, 243–254. 10.1038/nrmicro.2016.197
22
ColsonP.PagnierI.YoosufN.FournousG.La ScolaB.RaoultD. (2013). “Marseilleviridae,” a new family of giant viruses infecting amoebae. Arch. Virol.158, 915–920. 10.1007/s00705-012-1537-y
23
ColsonP.YutinN.ShabalinaS. A.RobertC.FournousG.La ScolaB.et al. (2011). Viruses with More Than 1,000 Genes: Mamavirus, a New Acanthamoeba polyphaga mimivirus Strain, and Reannotation of Mimivirus Genes. Genome Biol. Evol.3, 737–742. 10.1093/gbe/evr048
24
DereeperA.AudicS.ClaverieJ.-M.BlancG. (2010). BLAST-EXPLORER helps you building datasets for phylogenetic analysis. BMC Evol. Biol.10:8. 10.1186/1471-2148-10-8
25
DereeperA.GuignonV.BlancG.AudicS.BuffetS.ChevenetF.et al. (2008). Phylogeny.fr: robust phylogenetic analysis for the non-specialist. Nucleic Acids Res.36, W465–W469. 10.1093/nar/gkn180
26
DesnuesC.La ScolaB.YutinN.FournousG.RobertC.AzzaS.et al. (2012). Provirophages and transpovirons as the diverse mobilome of giant viruses. Proc. Natl. Acad. Sci. U.S.A.109, 18078–18083. 10.1073/pnas.1208835109
27
DesnuesC.RaoultD. (2012). Virophages question the existence of satellites. Nat. Rev. Microbiol.10:234. 10.1038/nrmicro2676-c3
28
DornasF. P.AssisF. L.AherfiS.ArantesT.AbrahãoJ. S.ColsonP.et al. (2016). A Brazilian Marseillevirus is the founding member of a lineage in family Marseilleviridae. Viruses8:76. 10.3390/v8030076
29
DornasF. P.KhalilJ. Y. B.PagnierI.RaoultD.AbrahãoJ.La ScolaB. (2015). Isolation of new Brazilian giant viruses from environmental samples using a panel of protozoa. Front. Microbiol.6:1086. 10.3389/fmicb.2015.01086
30
DornasF. P.RodriguesF. P.BorattoP. V. M.SilvaL. C. F.FerreiraP. C. P.BonjardimC. A.et al. (2014). Mimivirus circulation among wild and domestic mammals, Amazon Region, Brazil. Emerging Infect. Dis.20, 469–472. 10.3201/eid2003.131050
31
Dos SantosR. N.CamposF. S.Medeiros De AlbuquerqueN. R.FinokettiF.CôrreaR. A.Cano-OrtizL.et al. (2016). A new marseillevirus isolated in Southern Brazil from Limnoperna fortunei. Sci. Rep.6:35237. 10.1038/srep35237
32
DoutreG.ArfibB.RochetteP.ClaverieJ.-M.BoninP.AbergelC. (2015). Complete genome sequence of a new member of the Marseilleviridae recovered from the Brackish submarine spring in the Cassis Port-Miou Calanque, France. Genome Announc.3:e01148-15. 10.1128/genomeA.01148-15
33
DoutreG.PhilippeN.AbergelC.ClaverieJ.-M. (2014). Genome analysis of the first Marseilleviridae representative from Australia indicates that most of its genes contribute to virus fitness. J. Virol.88, 14340–14349. 10.1128/JVI.02414-14
34
FabreE.JeudyS.SantiniS.LegendreM.TrauchessecM.CoutéY.et al. (2017). Noumeavirus replication relies on a transient remote control of the host nucleus. Nat. Commun.8:15087. 10.1038/ncomms15087
35
FiléeJ.SiguierP.ChandlerM. (2007). I am what I eat and I eat what I am: acquisition of bacterial genes by giant viruses. Trends Genet.23, 10–15. 10.1016/j.tig.2006.11.002
36
FischerM. G. (2011). Sputnik and Mavirus: more than just satellite viruses. Nat. Rev. Microbiol.10:78. 10.1038/nrmicro2676-c1
37
FischerM. G.AllenM. J.WilsonW. H.SuttleC. A. (2010). Giant virus with a remarkable complement of genes infects marine zooplankton. Proc. Natl. Acad. Sci. U.S.A.107, 19508–19513. 10.1073/pnas.1007615107
38
FischerM. G.HacklT. (2016). Host genome integration and giant virus-induced reactivation of the virophage mavirus. Nature540:288. 10.1038/nature20593
39
FischerM. G.SuttleC. A. (2011). A virophage at the origin of large DNA transposons. Science332:231. 10.1126/science.1199412
40
ForterreP. (2010). Giant viruses: conflicts in revisiting the virus concept. Intervirology53, 362–378. 10.1159/000312921
41
GaiaM.BenamarS.BoughalmiM.PagnierI.CroceO.ColsonP.et al. (2014). Zamilon, a novel virophage with Mimiviridae host specificity. PLoS ONE9:e94923. 10.1371/journal.pone.0094923
42
GaiaM.PagnierI.CampocassoA.FournousG.RaoultD.La ScolaB. (2013). Broad spectrum of Mimiviridae virophage allows its isolation using a mimivirus reporter. PLoS ONE8:e61912. 10.1371/journal.pone.0061912
43
GhigoE.KartenbeckJ.LienP.PelkmansL.CapoC.MegeJ.-L.et al. (2008). Ameobal pathogen mimivirus infects macrophages through phagocytosis. PLoS Pathog.4:e1000087. 10.1371/journal.ppat.1000087
44
KhalilJ. Y. B.AndreaniJ.La ScolaB. (2016a). Updating strategies for isolating and discovering giant viruses. Curr. Opin. Microbiol.31, 80–87. 10.1016/j.mib.2016.03.004
45
KhalilJ. Y. B.RobertS.RetenoD. G.AndreaniJ.RaoultD.La ScolaB. (2016b). High-throughput isolation of giant viruses in liquid medium using automated flow cytometry and fluorescence staining. Front. Microbiol.7:26. 10.3389/fmicb.2016.00026
46
KloseT.HerbstD. A.ZhuH.MaxJ. P.KenttämaaH. I.RossmannM. G. (2015). A mimivirus enzyme that participates in viral entry. Structure23, 1058–1065. 10.1016/j.str.2015.03.023
47
KooninE. V.KrupovicM. (2017). Polintons, virophages and transpovirons: a tangled web linking viruses, transposons and immunity. Curr. Opin. Virol.25, 7–15. 10.1016/j.coviro.2017.06.008
48
KrupovicM.BamfordD. H.KooninE. V. (2014). Conservation of major and minor jelly-roll capsid proteins in Polinton (Maverick) transposons suggests that they are bona fide viruses. Biol. Direct9:6. 10.1186/1745-6150-9-6
49
KrupovicM.Cvirkaite-KrupovicV. (2011). Virophages or satellite viruses?Nat. Rev. Microbiol.9:762. 10.1038/nrmicro2676
50
KrupovicM.KuhnJ. H.FischerM. G. (2016). A classification system for virophages and satellite viruses. Arch. Virol.161, 233–247. 10.1007/s00705-015-2622-9
51
KuznetsovY. G.KloseT.RossmannM.McphersonA. (2013). Morphogenesis of mimivirus and its viral factories: an atomic force microscopy study of infected cells. J. Virol.87, 11200–11213. 10.1128/JVI.01372-13
52
LagierJ.-C.ArmougomF.MillionM.HugonP.PagnierI.RobertC.et al. (2012). Microbial culturomics: paradigm shift in the human gut microbiome study. Clin. Microbiol. Infect.18, 1185–1193. 10.1111/1469-0691.12023
53
La ScolaB.AudicS.RobertC.JungangL.LamballerieX. D.DrancourtM.et al. (2003). A giant virus in amoebae. Science299:2033. 10.1126/science.1081867
54
La ScolaB.CampocassoA.N'dongR.FournousG.BarrassiL.FlaudropsC.et al. (2010). Tentative characterization of new environmental giant viruses by MALDI-TOF mass spectrometry. Intervirology53, 344–353. 10.1159/000312919
55
La ScolaB.DesnuesC.PagnierI.RobertC.BarrassiL.FournousG.et al. (2008). The virophage as a unique parasite of the giant mimivirus. Nature455, 100–104. 10.1038/nature07218
56
LegendreM.SantiniS.RicoA.AbergelC.ClaverieJ.-M. (2011). Breaking the 1000-gene barrier for Mimivirus using ultra-deep genome and transcriptome sequencing. Virol. J.8:99. 10.1186/1743-422X-8-99
57
LwoffA. (1957). The concept of virus. J. Gen. Microbiol.17, 239–253. 10.1099/00221287-17-2-239
58
MoreiraD.Brochier-ArmanetC. (2008). Giant viruses, giant chimeras: the multiple evolutionary histories of Mimivirus genes. BMC Evol. Biol.8:12. 10.1186/1471-2148-8-12
59
MutsafiY.Fridmann-SirkisY.MilrotE.HevroniL.MinskyA. (2014). Infection cycles of large DNA viruses: emerging themes and underlying questions. Virology 466–467, 3–14. 10.1016/j.virol.2014.05.037
60
MutsafiY.ShimoniE.ShimonA.MinskyA. (2013). Membrane assembly during the infection cycle of the giant Mimivirus. PLoS Pathog.9:e1003367. 10.1371/journal.ppat.1003367
61
MutsafiY.ZaubermanN.SabanayI.MinskyA. (2010). Vaccinia-like cytoplasmic replication of the giant Mimivirus. Proc. Natl. Acad. Sci. U.S.A.107, 5978–5982. 10.1073/pnas.0912737107
62
OgataH.ClaverieJ.-M. (2008). How to infect a mimivirus. Science321:1305. 10.1126/science.1164839
63
OhJ.BroylesS. S. (2005). Host cell nuclear proteins are recruited to cytoplasmic vaccinia virus replication complexes. J. Virol.79, 12852–12860. 10.1128/JVI.79.20.12852-12860.2005
64
PagnierI.RetenoD.-G. I.SaadiH.BoughalmiM.GaiaM.SlimaniM.et al. (2013). A decade of improvements in Mimiviridae and Marseilleviridae isolation from amoeba. Intervirology56, 354–363. 10.1159/000354556
65
PopgeorgievN.BoyerM.FancelloL.MonteilS.RobertC.RivetR.et al. (2013). Marseillevirus-like virus recovered from blood donated by asymptomatic humans. J. Infect. Dis.208, 1042–1050. 10.1093/infdis/jit292
66
RaoultD. (2013). TRUC or the need for a new microbial classification. Intervirology56, 349–353. 10.1159/000354269
67
RaoultD.AudicS.RobertC.AbergelC.RenestoP.OgataH.et al. (2004). The 1.2-megabase genome sequence of Mimivirus. Science306, 1344–1350. 10.1126/science.1101485
68
RaoultD.ForterreP. (2008). Redefining viruses: lessons from Mimivirus. Nat. Rev. Microbiol.6, 315–319. 10.1038/nrmicro1858
69
RaoultD.La ScolaB.BirtlesR. (2007). The discovery and characterization of Mimivirus, the largest known virus and putative pneumonia agent. Clin. Infect. Dis.45, 95–102. 10.1086/518608
70
RenestoP.AbergelC.DecloquementP.MoinierD.AzzaS.OgataH.et al. (2006). Mimivirus giant particles incorporate a large fraction of anonymous and unique gene products. J. Virol.80, 11678–11685. 10.1128/JVI.00940-06
71
ReschW.HixsonK. K.MooreR. J.LiptonM. S.MossB. (2007). Protein composition of the vaccinia virus mature virion. Virology358, 233–247. 10.1016/j.virol.2006.08.025
72
RodriguesR. A. L.Dos Santos SilvaL. K.DornasF. P.OliveiraD. B. D.MagalhãesT. F. F.SantosD. A.et al. (2015). Mimivirus fibrils are important for viral attachment to the microbial world by a diverse glycoside interaction repertoire. J. Virol.89, 11812–11819. 10.1128/JVI.01976-15
73
SaadiH.PagnierI.ColsonP.CherifJ. K.BejiM.BoughalmiM.et al. (2013a). First isolation of mimivirus in a patient with pneumonia. Clin. Infect. Dis.57, e127–e134. 10.1093/cid/cit354
74
SaadiH.RetenoD. G. I.ColsonP.AherfiS.MinodierP.PagnierI.et al. (2013b). Shan virus: a new mimivirus isolated from the stool of a Tunisian Patient with pneumonia. Intervirology56, 424–429. 10.1159/000354564
75
SilvaL. C. F.AlmeidaG. M. F.OliveiraD. B.DornasF. P.CamposR. K.La ScolaB.et al. (2014). A resourceful giant: APMV is able to interfere with the human type I interferon system. Microbes Infect.16, 187–195. 10.1016/j.micinf.2013.11.011
76
SobhyH.La ScolaB.PagnierI.RaoultD.ColsonP. (2015). Identification of giant Mimivirus protein functions using RNA interference. Front. Microbiol.6:345. 10.3389/fmicb.2015.00345
77
SuhreK. (2005). Gene and genome duplication in Acanthamoeba polyphaga Mimivirus. J. Virol.79, 14095–14101. 10.1128/JVI.79.22.14095-14101.2005
78
SuhreK.AudicS.ClaverieJ.-M. (2005). Mimivirus gene promoters exhibit an unprecedented conservation among all eukaryotes. Proc. Natl. Acad. Sci. U.S.A.102, 14689–14693. 10.1073/pnas.0506465102
79
Suzan-MontiM.La ScolaB.BarrassiL.EspinosaL.RaoultD. (2007). Ultrastructural characterization of the giant volcano-like virus factory of Acanthamoeba polyphaga Mimivirus. PLoS ONE2:e328. 10.1371/journal.pone.0000328
80
TakemuraM. (2016). Draft genome sequence of tokyovirus, a member of the family Marseilleviridae Isolated from the Arakawa River of Tokyo, Japan. Genome Announc.4:e00429-16. 10.1128/genomeA.00429-16
81
TakemuraM.MikamiT.MuronoS. (2016). Nearly complete genome sequences of two mimivirus strains isolated from a Japanese Freshwater Pond and River Mouth. Genome Announc.4:e01378-16. 10.1128/genomeA.01378-16
82
ThomasV.BertelliC.CollynF.CassonN.TelentiA.GoesmannA.et al. (2011). Lausannevirus, a giant amoebal virus encoding histone doublets. Environ. Microbiol.13, 1454–1466. 10.1111/j.1462-2920.2011.02446.x
83
XiaoC.KuznetsovY. G.SunS.HafensteinS. L.KostyuchenkoV. A.ChipmanP. R.et al. (2009). Structural studies of the giant mimivirus. PLoS Biol.7:e92. 10.1371/journal.pbio.1000092
84
YauS.LauroF. M.DemaereM. Z.BrownM. V.ThomasT.RafteryM. J.et al. (2011). Virophage control of antarctic algal host–virus dynamics. Proc. Natl. Acad. Sci. U.S.A.108, 6163–6168. 10.1073/pnas.1018221108
85
YoosufN.PagnierI.FournousG.RobertC.La ScolaB.RaoultD.et al. (2014a). Complete genome sequence of Courdo11 virus, a member of the family Mimiviridae. Virus Genes48, 218–223. 10.1007/s11262-013-1016-x
86
YoosufN.PagnierI.FournousG.RobertC.RaoultD.La ScolaB.et al. (2014b). Draft genome sequences of Terra1 and Terra2 viruses, new members of the family Mimiviridae isolated from soil. Virology 452–453, 125–132. 10.1016/j.virol.2013.12.032
87
YoosufN.YutinN.ColsonP.ShabalinaS. A.PagnierI.RobertC.et al. (2012). Related giant viruses in distant locations and different habitats: Acanthamoeba polyphaga moumouvirus represents a third lineage of the Mimiviridae that is close to the megavirus lineage. Genome Biol. Evol.4, 1324–1330. 10.1093/gbe/evs109
88
YutinN.KooninE. V. (2012). Hidden evolutionary complexity of Nucleo-Cytoplasmic Large DNA viruses of eukaryotes. Virol. J.9:161. 10.1186/1743-422X-9-161
89
YutinN.RaoultD.KooninE. V. (2013). Virophages, polintons, and transpovirons: a complex evolutionary network of diverse selfish genetic elements with different reproduction strategies. Virol. J.10:158. 10.1186/1743-422X-10-158
90
YutinN.WolfY. I.RaoultD.KooninE. V. (2009). Eukaryotic large nucleo-cytoplasmic DNA viruses: clusters of orthologous genes and reconstruction of viral genome evolution. Virol. J.6:223. 10.1186/1743-422X-6-223
91
ZaubermanN.MutsafiY.HalevyD. B.ShimoniE.KleinE.XiaoC.et al. (2008). Distinct DNA exit and packaging portals in the virus Acanthamoeba polyphaga mimivirus. PLoS Biol.6:e114. 10.1371/journal.pbio.0060114
92
ZhouJ.SunD.ChildersA.McdermottT. R.WangY.LilesM. R. (2015). Three novel virophage genomes discovered from Yellowstone Lake metagenomes. J. Virol.89, 1278–1285. 10.1128/JVI.03039-14
93
ZhouJ.ZhangW.YanS.XiaoJ.ZhangY.LiB.et al. (2013). Diversity of virophages in metagenomic data sets. J. Virol.87, 4225–4236. 10.1128/JVI.03398-12
Summary
Keywords
Acanthamoeba polyphaga mimivirus (APMV), virophage, nucleocytoplasmatic large DNA virus (NCLDV), mimivirus, pathogen defense
Citation
Diesend J, Kruse J, Hagedorn M and Hammann C (2018) Amoebae, Giant Viruses, and Virophages Make Up a Complex, Multilayered Threesome. Front. Cell. Infect. Microbiol. 7:527. doi: 10.3389/fcimb.2017.00527
Received
15 October 2017
Accepted
13 December 2017
Published
11 January 2018
Volume
7 - 2017
Edited by
Thierry Soldati, Université de Genève, Switzerland
Reviewed by
Guruprasad R. Medigeshi, Translational Health Science and Technology Institute, India; Bernard La Scola, Aix-Marseille University, France
Updates
Copyright
© 2018 Diesend, Kruse, Hagedorn and Hammann.
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) or licensor 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.
*Correspondence: Christian Hammann c.hammann@jacobs-university.de
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