An Invertron-Like Linear Plasmid Mediates Intracellular Survival and Virulence in Bovine Isolates of Rhodococcus equi

Valero-Rello, Ana; Hapeshi, Alexia; Anastasi, Elisa; Alvarez, Sonsiray; Scortti, Mariela; Meijer, Wim G.; MacArthur, Iain; Vázquez‐Boland, José A.

doi:10.1128/iai.00376-15

Cited by 67 publications

(154 citation statements)

References 71 publications

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“…The distribution of the host-associated virulence plasmid types in the R. equi phylogeny is consistent with the dynamic conjugal exchange of the plasmids across the R. equi population (Tripathi et al 2012; Valero-Rello et al 2015) and their key role in animal host tropism (Vazquez-Boland et al 2013; Valero-Rello et al 2015). Strains sharing the same core and accessory genomotype and virulence plasmid type were associated with both the corresponding adapted animal host and people (e.g., pVAPB-carrying 1413 and 1533 isolates, pVAPN-carrying 1354 and 1557 isolates) (fig.…”

Section: Discussionsupporting

confidence: 65%

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Pangenome and Phylogenomic Analysis of the Pathogenic ActinobacteriumRhodococcus equi

et al. 2016

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We report a comparative study of 29 representative genomes of the animal pathogen Rhodococcus equi. The analyses showed that R. equi is genetically homogeneous and clonal, with a large core genome accounting for ≈80% of an isolates’ gene content. An open pangenome, even distribution of accessory genes among the isolates, and absence of significant core–genome recombination, indicated that gene gain/loss is a main driver of R. equi genome evolution. Traits previously predicted to be important in R. equi physiology, virulence and niche adaptation were part of the core genome. This included the lack of a phosphoenolpyruvate:carbohydrate transport system (PTS), unique among the rhodococci except for the closely related Rhodococcus defluvii, reflecting selective PTS gene loss in the R. equi–R. defluvii sublineage. Thought to be asaccharolytic, rbsCB and glcP non-PTS sugar permease homologues were identified in the core genome and, albeit inefficiently, R. equi utilized their putative substrates, ribose and (irregularly) glucose. There was no correlation between R. equi whole-genome phylogeny and host or geographical source, with evidence of global spread of genomovars. The distribution of host-associated virulence plasmid types was consistent with the exchange of the plasmids (and corresponding host shifts) across the R. equi population, and human infection being zoonotically acquired. Phylogenomic analyses demonstrated that R. equi occupies a central position in the Rhodococcus phylogeny, not supporting the recently proposed transfer of the species to a new genus.

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Section: Discussionsupporting

confidence: 65%

“…Isolates of different animal sources (equine, bovine, porcine, ovine, human), geographical origin (13 countries) and host-associated virulence plasmid type carriage (pVAPA, pVAPB, pVAPN) (Takai et al 2000; Letek et al 2008; Valero-Rello et al 2015) were analyzed.…”

Section: Methodsmentioning

confidence: 99%

Pangenome and Phylogenomic Analysis of the Pathogenic ActinobacteriumRhodococcus equi

et al. 2016

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“…The identical 17-gene insertion in pVAPB1413 and pVAP1533 is also at the right end of the vapB PAI adjacent to the invA gene; it encodes two transposases, a TnB transposition protein and a phage integrase, plus a bleomycin resistance determinant, an MFS transporter, and β-oxidation catabolic enzymes with closest homologs in other rhodococci. Most pVAPN plasmids (not at scale) are identical to the reference sequence except for two additional CDSs near the left telomere (Valero-Rello et al 2015). Blue lines joining the termini indicate the telomeric inverted repeats.…”

Section: Resultsmentioning

confidence: 99%

“…This further supports the notion that the rep - parA determinant of the Rhodococcus plasmids (often identified as horizontal gene transfer [HGT] DNA) is part of a highly plastic, horizontally exchangeable plasmid region (Letek et al. 2008; Valero-Rello et al. 2015).…”

Section: Resultsmentioning

confidence: 99%

Comparative Genomics of Rhodococcus equi Virulence Plasmids Indicates Host-Driven Evolution of the vap Pathogenicity Island

MacArthur

Anastasi

Alvarez

et al. 2017

Genome Biology and Evolution

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The conjugative virulence plasmid is a key component of the Rhodococcus equi accessory genome essential for pathogenesis. Three host-associated virulence plasmid types have been identified: the equine pVAPA and porcine pVAPB circular variants, and the linear pVAPN found in bovine (ruminant) isolates. We recently characterized the R. equi pangenome (Anastasi E, et al. 2016. Pangenome and phylogenomic analysis of the pathogenic actinobacterium Rhodococcus equi. Genome Biol Evol. 8:3140–3148.) and we report here the comparative analysis of the virulence plasmid genomes. Plasmids within each host-associated type were highly similar despite their diverse origins. Variation was accounted for by scattered single nucleotide polymorphisms and short nucleotide indels, while larger indels—mostly in the plasticity region near the vap pathogencity island (PAI)—defined plasmid genomic subtypes. Only one of the plasmids analyzed, of pVAPN type, was exceptionally divergent due to accumulation of indels in the housekeeping backbone. Each host-associated plasmid type carried a unique PAI differing in vap gene complement, suggesting animal host-specific evolution of the vap multigene family. Complete conservation of the vap PAI was observed within each host-associated plasmid type. Both diversity of host-associated plasmid types and clonality of specific chromosomal-plasmid genomic type combinations were observed within the same R. equi phylogenomic subclade. Our data indicate that the overall strong conservation of the R. equi host-associated virulence plasmids is the combined result of host-driven selection, lateral transfer between strains, and geographical spread due to international livestock exchanges.

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“…R. equi is an intracellular pathogen (Hietala & Ardans, 1987;Hondalus & Mosser, 1994;Zink, Yager, Prescott, & Fernando, 1987), which frequently causes bronchopneumonia in horse foals and lifethreatening infections in AIDS patients (Prescott, 1991;Yamshchikov, Schuetz, & Lyon, 2010). Whereas VapA is tightly associated with foal disease, isolates from mammals other than horses can contain plasmids with VapA homologues (Makrai et al, 2002;Valero-Rello et al, 2015). Whereas VapA is tightly associated with foal disease, isolates from mammals other than horses can contain plasmids with VapA homologues (Makrai et al, 2002;Valero-Rello et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Virulence‐associated protein A fromRhodococcus equiis an intercompartmental pH‐neutralising virulence factor

Bargen

Scraba

Krämer

et al. 2018

Cellular Microbiology

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Professional phagocytic cells such as macrophages are a central part of innate immune defence. They ingest microorganisms into membrane-bound compartments (phagosomes), which acidify and eventually fuse with lysosomes, exposing their contents to a microbicidal environment. Gram-positive Rhodococcus equi can cause pneumonia in young foals and in immunocompromised humans. The possession of a virulence plasmid allows them to subvert host defence mechanisms and to multiply in macrophages. Here, we show that the plasmid-encoded and secreted virulenceassociated protein A (VapA) participates in exclusion of the proton-pumping vacuolar-ATPase complex from phagosomes and causes membrane permeabilisation, thus contributing to a pH-neutral phagosome lumen. Using fluorescence and electron microscopy, we show that VapA is also transferred from phagosomes to lysosomes where it permeabilises the limiting membranes for small ions such as protons. This permeabilisation process is different from that of known membrane pore formers as revealed by experiments with artificial lipid bilayers. We demonstrate that, at 24 hr of infection, virulent R. equi is contained in a vacuole, which is enriched in lysosome material, yet possesses a pH of 7.2 whereas phagosomes containing a vapA deletion mutant have a pH of 5.8 and those with virulence plasmid-less sister strains have a pH of 5.2. Experimentally neutralising the macrophage endocytic system allows avirulent R. equi to multiply. This observation is mirrored in the fact that virulent and avirulent R. equi multiply well in extracts of purified lysosomes at pH 7.2 but not at pH 5.1. Together these data indicate that the major function of VapA is to generate a pH-neutral and hence growth-promoting intracellular niche. VapA represents a new type of Gram-positive virulence factor by trafficking from one subcellular compartment to another, affecting membrane permeability, excluding proton-pumping ATPase, and consequently disarming host defences.

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An Invertron-Like Linear Plasmid Mediates Intracellular Survival and Virulence in Bovine Isolates of Rhodococcus equi

Cited by 67 publications

References 71 publications

Pangenome and Phylogenomic Analysis of the Pathogenic ActinobacteriumRhodococcus equi

Pangenome and Phylogenomic Analysis of the Pathogenic ActinobacteriumRhodococcus equi

Comparative Genomics of Rhodococcus equi Virulence Plasmids Indicates Host-Driven Evolution of the vap Pathogenicity Island

Virulence‐associated protein A fromRhodococcus equiis an intercompartmental pH‐neutralising virulence factor

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