Degradation-resistant protein domains limit host cell processing and immune detection of mycobacteria

Koh, Kah Wee; Lehming, Norbert; Seah, Geok Teng

doi:10.1016/j.molimm.2008.11.008

Cited by 32 publications

(20 citation statements)

References 42 publications

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“…The absence of selection exerted on pe/ppe genes may be interpreted as both a result of immune pressure selecting for antigenic variants and an adaptation for these proteins to function alongside new or rare MHC alleles that have not previously been encountered in the bacteria's evolutionary history. Although purely speculative, this theory is consistent with the large pe/ppe expansion within the MTBC (and in the closely related species M. marinum which is a natural pathogen of fish), it's functional and expressional variability, and the finding that some pe/ppe proteins appear to interfere with antigen processing [43], [44]. The true nature of pe/ppe function remains one of the great mysteries of M. tuberculosis pathogenesis however and many additional functional studies will probably be required before we are able to gain a more complete understanding of their role.…”

Section: Discussionsupporting

confidence: 54%

“…This leads to an anti-inflammatory Th2 type immune response. Evidence also exists to suggest that pe_pgrs proteins may be able to inhibit antigen processing and/or presentation [43] and it has been proposed that the Gly-Ala repeats in the C-terminal PGRS domains are able to inhibit proteasomal degradation of the N-terminal PE domain [44] thus inhibiting antigen processing by CD8+ T cells in a manner similar to that seen in Epstein – Barr virus nuclear antigen 1 [45]. Several other lines of evidence also suggest a major role for pe/ppe proteins in mycobacterial pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Analysis of Mycobacterium tuberculosis pe and ppe Genes Reveals High Sequence Variation and an Apparent Absence of Selective Constraints

et al. 2012

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Mycobacterium tuberculosis complex (MTBC) genomes contain 2 large gene families termed pe and ppe . The function of pe/ppe proteins remains enigmatic but studies suggest that they are secreted or cell surface associated and are involved in bacterial virulence. Previous studies have also shown that some pe / ppe genes are polymorphic, a finding that suggests involvement in antigenic variation. Using comparative sequence analysis of 18 publicly available MTBC whole genome sequences, we have performed alignments of 33 pe (excluding pe_pgrs ) and 66 ppe genes in order to detect the frequency and nature of genetic variation. This work has been supplemented by whole gene sequencing of 14 pe / ppe (including 5 pe_pgrs ) genes in a cohort of 40 diverse and well defined clinical isolates covering all the main lineages of the M. tuberculosis phylogenetic tree. We show that nsSNP's in pe (excluding pgrs ) and ppe genes are 3.0 and 3.3 times higher than in non- pe / ppe genes respectively and that numerous other mutation types are also present at a high frequency. It has previously been shown that non- pe / ppe M. tuberculosis genes display a remarkably low level of purifying selection. Here, we also show that compared to these genes those of the pe / ppe families show a further reduction of selection pressure that suggests neutral evolution. This is inconsistent with the positive selection pressure of “classical” antigenic variation. Finally, by analyzing such a large number of genes we were able to detect large differences in mutation type and frequency between both individual genes and gene sub-families. The high variation rates and absence of selective constraints provides valuable insights into potential pe/ppe function. Since pe/ppe proteins are highly antigenic and have been studied as potential vaccine components these results should also prove informative for aspects of M. tuberculosis vaccine design.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of Mycobacterium tuberculosis pe and ppe Genes Reveals High Sequence Variation and an Apparent Absence of Selective Constraints

et al. 2012

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“…The observation that PE_PGRS proteins bear some resemblance to the Epstein-Barr virus nuclear antigen (EBVNA) gave rise to speculation that, akin to the EBVNA, the PE_PGRS proteins may inhibit antigen processing [5]. This has subsequently been demonstrated for PE_PGRS33 [48] and PE_PGRS17 [74], supporting the idea that these proteins may assist in immune evasion by limiting antigen presentation, thereby preventing recognition and killing of mycobacteria-infected host cells.…”

Section: Pe/ppes Modulate Innate Immune Responsesmentioning

confidence: 99%

Mycobacterial PE/PPE Proteins at the Host-Pathogen Interface

Sampson

2011

Clinical and Developmental Immunology

228

225

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The mycobacterial PE/PPE proteins have attracted much interest since their formal identification just over a decade ago. It has been widely speculated that these proteins may play a role in evasion of host immune responses, possibly via antigenic variation. Although a cohesive understanding of their function(s) has yet to be established, emerging data increasingly supports a role for the PE/PPE proteins at multiple levels of the infectious process. This paper will delineate salient features of the families revealed by comparative genomics, bioinformatic analyses and genome-wide screening approaches and will summarise existing knowledge of subcellular localization, secretion pathways, and protein structure. These characteristics will be considered in light of findings on innate and adaptive host responses to PE/PPE proteins, and we will review the increasing body of data on B and T cell recognition of these proteins. Finally, we will consider how current knowledge and future explorations may contribute to a more comprehensive understanding of these intriguing proteins and their involvement in host pathogen interactions. Ultimately this information could underpin future intervention strategies, for example, in the area of new and improved diagnostic tools and vaccine candidates.

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“…A recent report indicated the role of one such ubiquitin protease during M. tuberculosis infection, wherein some of the PE-polymorphic CG-proteins of M. tuberculosis were found to be resistant to these proteases (35). However, their roles in specifically regulating M. tuberculosis survival have not been reported.…”

Section: Genes Of Calcium Calmodulin and Cysteine Protease Pathways Mmentioning

confidence: 99%

Suppression of Dendritic Cell-mediated Responses by Genes in Calcium and Cysteine Protease Pathways during Mycobacterium tuberculosis Infection

Singhal

Agrawal

Vashishta

et al. 2012

Journal of Biological Chemistry

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Background: RNA interference (RNAi) is a useful tool to know the function of a gene in a cell under any kind of stress. Results: RNAi-mediated knockdown of genes in dendritic cells identified unreported genes and pathways that regulate its various functions during Mycobacterium tuberculosis infection. Conclusion:The identified genes could be potential targets in drug and vaccine designing. Significance: Understanding the role of host factors that regulate priming of immune responses is crucial to study hostpathogen interactions.

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Degradation-resistant protein domains limit host cell processing and immune detection of mycobacteria

Cited by 32 publications

References 42 publications

Comparative Analysis of Mycobacterium tuberculosis pe and ppe Genes Reveals High Sequence Variation and an Apparent Absence of Selective Constraints

Comparative Analysis of Mycobacterium tuberculosis pe and ppe Genes Reveals High Sequence Variation and an Apparent Absence of Selective Constraints

Mycobacterial PE/PPE Proteins at the Host-Pathogen Interface

Suppression of Dendritic Cell-mediated Responses by Genes in Calcium and Cysteine Protease Pathways during Mycobacterium tuberculosis Infection

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