Frequent Homologous Recombination Events in
            <i>Mycobacterium tuberculosis</i>
            PE/PPE Multigene Families: Potential Role in Antigenic Variability

Karboul, Anis; Mazza, Alberto; Pittius, Nicolaas C. Gey van; Ho, John L.; Brousseau, Roland; Mardassi, Helmi

doi:10.1128/jb.00827-08

Cited by 67 publications

(53 citation statements)

References 55 publications

(40 reference statements)

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“…It is not surprising that several PE/PPE genes, including PPE38, PE_PGRS33, PE_PGRS16, and PE_PGRS26, were found to exhibit extensive polymorphisms in clinical isolates of M. tuberculosis (41,47,66,67). Consequently, it was speculated that these proteins represent a source of antigenic variation which allows the pathogen to evade antigen-specific host responses (22,41,66).…”

Section: Discussionmentioning

confidence: 99%

PPE38 Modulates the Innate Immune Response and Is Required for Mycobacterium marinum Virulence

Dong

Wang

et al. 2012

Infect Immun

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The proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) family proteins are prevalent in pathogenic mycobacteria and play a diverse role in mycobacterial pathogenesis. While some members have been studied, the function of most PE/PPE proteins remains unknown. In this study, we isolated a transposon-inactivated PPE38 mutant of Mycobacterium marinum and characterized its phenotype. We found that the PPE38 protein is associated with the cell wall and exposed on the cell surface. The inactivation of PPE38 altered the bacterial cell surface properties and led to deficiencies in cord formation, sliding motility, and biofilm formation. The PPE38 mutant was defective in phagocytosis by macrophages and exhibited reduced virulence in adult zebrafish. We also found that PPE38 is involved in the induction of proinflammatory cytokines in infected macrophages. Together, our results indicate that PPE38, a previously uncharacterized protein, plays a role in mycobacterial virulence, presumably by modulating the host innate immune response. Mycobacterium tuberculosis is a highly successful human pathogen that latently infects one-third of the world's population, causing 10 million new infections and 2 million deaths annually. One reason for the success of M. tuberculosis lies in its ability to evade host immune defense mechanisms and to create a niche within host cells, enabling the bacterium to persist for long periods. M. tuberculosis infects and survives within macrophages by evading macrophage killing mechanisms through a variety of strategies (reviewed in references 51 and 56). During persistent infection, M. tuberculosis is thought to reside within a granuloma, a cellular accumulation around the bacilli that is comprised mainly of macrophages, dendritic cells, T cells, B cells, and fibroblasts (reviewed in reference 31). Granulomas are generally thought to contain the infection by limiting bacterial growth and spread (21, 61). However, recent studies by Ramakrishnan and coworkers using zebrafish embryos demonstrated that the granuloma is a dynamic structure and that Mycobacterium marinum, an aquatic mycobacterium closely related to M. tuberculosis, uses the granuloma as a niche to recruit uninfected macrophages, raising the possibility that granulomas are exploited by the pathogen for expansion and dissemination in early infection (23,25,26).PE and PPE family proteins, named for the conserved N-terminal-domain-containing proline-glutamic acid (PE) motif or proline-proline-glutamine (PPE) motif, are unique to mycobacteria and particularly prevalent in pathogenic mycobacteria (35). They account for a significant fraction (ϳ10%) of the coding capacity of pathogenic mycobacteria. There are 168 PE/PPE proteins in M. tuberculosis (22) and 281 in M. marinum (64). The relatively conserved N termini are approximately 110 and 180 amino acids in the PE and PPE families, respectively. The C-terminal domains of both the PE and PPE protein families are highly variable in both size and sequence and often contain repetitive ...

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Section: Discussionmentioning

confidence: 99%

PPE38 Modulates the Innate Immune Response and Is Required for Mycobacterium marinum Virulence

Dong

Wang

et al. 2012

Infect Immun

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“…This includes the highly GC-rich and polymorphic PE/PPE gene family, esx genes, and Insertion Sequences. Gene conversion resulting from frequent intrachromosomal homologous recombination has been reported between members of each of these families (Ho et al 2000;McEvoy et al 2007;Karboul et al 2008;Uplekar et al 2011). Hence, exclusion of these regions prevents spurious inclusion of intrachromosomal recombination events in the analyses of recombination presented below.…”

Section: Whole-genome Snp Discovery and Phylogeny Of Mtbc Strainsmentioning

confidence: 99%

After the bottleneck: Genome-wide diversification of the Mycobacterium tuberculosis complex by mutation, recombination, and natural selection

Namouchi¹,

Didelot²,

Schöck³

et al. 2012

Genome Res.

147

122

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Many of the most virulent bacterial pathogens show low genetic diversity and sexual isolation. Accordingly, Mycobacterium tuberculosis, the deadliest human pathogen, is thought to be clonal and evolve by genetic drift. Yet, its genome shows few of the concomitant signs of genome degradation. We analyzed 24 genomes and found an excess of genetic diversity in regions encoding key adaptive functions including the type VII secretion system and the ancient horizontally transferred virulence-related regions. Four different approaches showed evident signs of recombination in M. tuberculosis. Recombination tracts add a high density of polymorphisms, and many are thus predicted to arise from outside the clade. Some of these tracts match Mycobacterium canettii sequences. Recombination introduced an excess of non-synonymous diversity in general and even more in genes expected to be under positive or diversifying selection, e.g., cell wall component genes. Mutations leading to non-synonymous SNPs are effectively purged in MTBC, which shows dominance of purifying selection. MTBC mutation bias toward AT nucleotides is not compensated by biased gene conversion, suggesting the action of natural selection also on synonymous changes. Together, all of these observations point to a strong imprint of recombination and selection in the genome affecting both non-synonymous and synonymous positions. Hence, contrary to some other pathogens and previous proposals concerning M. tuberculosis, this lineage may have come out of its ancestral bottleneck as a very successful pathogen that is rapidly diversifying by the action of mutation, recombination, and natural selection.

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“…This theory has been fueled by observations that there is variation in certain pe_pgrs gene sequences among clinical isolates (10,11) and that recombination leading to gene deletions can occur between different copies of the pe and ppe genes (12). There is, however, little evidence to support rapid alterations of pe and ppe gene sequences in vivo (13).…”

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confidence: 99%

Mycobacterium tuberculosis Resists Stress by Regulating PE19 Expression

et al. 2016

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cMycobacterium tuberculosis requires the phosphate-sensing signal transduction system Pst/SenX3-RegX3 to resist host immune responses. A ⌬pstA1 mutant lacking a Pst phosphate uptake system component is hypersensitive to diverse stress conditions in vitro and is attenuated in vivo due to constitutive expression of the phosphate starvation-responsive RegX3 regulon. Transcriptional profiling of the ⌬pstA1 mutant revealed aberrant expression of certain pe and ppe genes. PE and PPE proteins, defined by conserved N-terminal domains containing Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs, account for a substantial fraction of the M. tuberculosis genome coding capacity, but their functions are largely uncharacterized. Because some PE and PPE proteins localize to the cell wall, we hypothesized that overexpression of these proteins sensitizes M. tuberculosis to stress by altering cell wall integrity. To test this idea, we deleted pe and ppe genes that were overexpressed by ⌬pstA1 bacteria. Deletion of a single pe gene, pe19, suppressed hypersensitivity of the ⌬pstA1 mutant to both detergent and reactive oxygen species. Ethidium bromide uptake assays revealed increased envelope permeability of the ⌬pstA1 mutant that was dependent on PE19. The replication defect of the ⌬pstA1 mutant in NOS2 ؊/؊ mice was partially reversed by deletion of pe19, suggesting that increased membrane permeability due to PE19 overexpression sensitizes M. tuberculosis to host immunity. Our data indicate that PE19, which comprises only a 99-amino-acid PE domain, has a unique role in the permeability of the M. tuberculosis envelope that is regulated to resist stresses encountered in the host. O ver 15 years ago, the novel PE and PPE protein families were identified in the complete genome sequence of Mycobacterium tuberculosis; together, these proteins represent over 7% of the genome coding capacity (1). Despite the attention placed on these protein families, their functions remain largely uncharacterized. PE and PPE proteins are defined by conserved N-terminal domains of ϳ110 or ϳ180 amino acids that contain Pro-Glu (PE) or Pro-Pro-Glu (PPE) sequence motifs, respectively (1). Although PE and PPE proteins can be identified in the genomes of all sequenced members of the Mycobacterium genus, their expansion into large multiprotein families is restricted to the slow-growing pathogenic mycobacterial species, including M. tuberculosis, and associated with the expansion of the ESX type VII secretion systems (2). There is evidence that some PE and PPE proteins are exported to the bacterial cell surface or extracellular milieu in an ESX-dependent manner (3-6). ESX-dependent export requires specific sequences within the PE or PPE domain (7, 8), including a recently described YxxxD/E ESX secretion targeting motif located near the C terminus of the ϳ110-amino-acid PE domain (9).The 99 PE proteins and 69 PPE proteins encoded by the M. tuberculosis H37Rv genome can be further divided into subfamilies based on C-terminal sequence motifs (2). The PE_PGRS (polymorphic GC-...

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Frequent Homologous Recombination Events in Mycobacterium tuberculosis PE/PPE Multigene Families: Potential Role in Antigenic Variability

Cited by 67 publications

References 55 publications

PPE38 Modulates the Innate Immune Response and Is Required for Mycobacterium marinum Virulence

PPE38 Modulates the Innate Immune Response and Is Required for Mycobacterium marinum Virulence

After the bottleneck: Genome-wide diversification of the Mycobacterium tuberculosis complex by mutation, recombination, and natural selection

Mycobacterium tuberculosis Resists Stress by Regulating PE19 Expression

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