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      The Enigmatic PE/PPE Multigene Family of Mycobacteria and Tuberculosis Vaccination

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      Journal: Infection and Immunity
      Publisher: American Society for Microbiology
      Keywords: tuberculosis, PE/PPE family of genes, vaccines

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          ABSTRACT

          The genome of Mycobacterium tuberculosis, the bacterium responsible for the disease tuberculosis, contains an unusual family of abundant antigens (PE/PPEs). To date, certain members of this multigene family occur only in mycobacteria that cause disease. It is possible that the numerous proteins encoded by these mycobacterial genes dictate the immune pathogenesis of this bacterial pathogen. There is also evidence that some of these antigens are present at the cell surface and that they affect the pathology and immunology of the organism in many ways. Also, they elicit both antibodies and T cells, they may be involved in antigenic variation, and they may be good candidates for vaccines and drugs. However, since they are plentiful and extremely homologous, these PE/PPEs are very challenging to study, and it is difficult to be certain what role(s) they have in the pathogenesis of tuberculosis. Consequently, how to develop treatments like vaccines using these antigens as candidates is complex.

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          Toward the structural genomics of complexes: crystal structure of a PE/PPE protein complex from Mycobacterium tuberculosis.

          Michael Strong, Michael R. Sawaya, Shuishu Wang … (2006)
          The developing science called structural genomics has focused to date mainly on high-throughput expression of individual proteins, followed by their purification and structure determination. In contrast, the term structural biology is used to denote the determination of structures, often complexes of several macromolecules, that illuminate aspects of biological function. Here we bridge structural genomics to structural biology with a procedure for determining protein complexes of previously unknown function from any organism with a sequenced genome. From computational genomic analysis, we identify functionally linked proteins and verify their interaction in vitro by coexpression/copurification. We illustrate this procedure by the structural determination of a previously unknown complex between a PE and PPE protein from the Mycobacterium tuberculosis genome, members of protein families that constitute approximately 10% of the coding capacity of this genome. The predicted complex was readily expressed, purified, and crystallized, although we had previously failed in expressing individual PE and PPE proteins on their own. The reason for the failure is clear from the structure, which shows that the PE and PPE proteins mate along an extended apolar interface to form a four-alpha-helical bundle, where two of the alpha-helices are contributed by the PE protein and two by the PPE protein. Our entire procedure for the identification, characterization, and structural determination of protein complexes can be scaled to a genome-wide level.
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            Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions

            Nicolaas Gey van Pittius, Samantha L. Sampson, Hyeyoung Lee … (2006)
            Background The PE and PPE multigene families of Mycobacterium tuberculosis comprise about 10% of the coding potential of the genome. The function of the proteins encoded by these large gene families remains unknown, although they have been proposed to be involved in antigenic variation and disease pathogenesis. Interestingly, some members of the PE and PPE families are associated with the ESAT-6 (esx) gene cluster regions, which are regions of immunopathogenic importance, and encode a system dedicated to the secretion of members of the potent T-cell antigen ESAT-6 family. This study investigates the duplication characteristics of the PE and PPE gene families and their association with the ESAT-6 gene clusters, using a combination of phylogenetic analyses, DNA hybridization, and comparative genomics, in order to gain insight into their evolutionary history and distribution in the genus Mycobacterium. Results The results showed that the expansion of the PE and PPE gene families is linked to the duplications of the ESAT-6 gene clusters, and that members situated in and associated with the clusters represent the most ancestral copies of the two gene families. Furthermore, the emergence of the repeat protein PGRS and MPTR subfamilies is a recent evolutionary event, occurring at defined branching points in the evolution of the genus Mycobacterium. These gene subfamilies are thus present in multiple copies only in the members of the M. tuberculosis complex and close relatives. The study provides a complete analysis of all the PE and PPE genes found in the sequenced genomes of members of the genus Mycobacterium such as M. smegmatis, M. avium paratuberculosis, M. leprae, M. ulcerans, and M. tuberculosis. Conclusion This work provides insight into the evolutionary history for the PE and PPE gene families of the mycobacteria, linking the expansion of these families to the duplications of the ESAT-6 (esx) gene cluster regions, and showing that they are composed of subgroups with distinct evolutionary (and possibly functional) differences.
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              PPE and PE_PGRS proteins of Mycobacterium marinum are transported via the type VII secretion system ESX-5.

              A. J. Brennan, Connie Jimenez, Nathalie Cadieux … (2009)
              ESX-5 is one of the five type VII secretion systems found in mycobacteria. These secretion systems are also known as ESAT-6-like secretion systems. Here, we have determined the secretome of ESX-5 by a proteomic approach in two different strains of Mycobacterium marinum. Comparison of the secretion profile of wild-type strains and their ESX-5 mutants showed that a number of PE_PGRS and PPE-MPTR proteins are dependent on ESX-5 for transport. The PE and PPE protein families are unique to mycobacteria, are highly expanded in several pathogenic species, such as Mycobacterium tuberculosis and M. marinum, and certain family members are cell surface antigens associated with virulence. Using a monoclonal antibody directed against the PGRS domain we showed that nearly all PE_PGRS proteins that are recognized by this antibody are missing in the supernatant of ESX-5 mutants. In addition to PE_PGRS and PPE proteins, the ESX-5 secretion system is responsible for the secretion of a ESAT-6-like proteins. Together, these data show that ESX-5 is probably a major secretion pathway for mycobacteria and that this system is responsible for the secretion of recently evolved PE_PGRS and PPE proteins.
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                Author and article information

                Contributors
                Anthony T. Maurelli: Role: Editor
                Journal
                Journal ID (nlm-ta): Infect Immun
                Journal ID (iso-abbrev): Infect. Immun
                Journal ID (hwp): iai
                Journal ID (pmc): iai
                Journal ID (publisher-id): IAI
                Title: Infection and Immunity
                Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )
                ISSN (Print): 0019-9567
                ISSN (Electronic): 1098-5522
                Publication date (Electronic preprint): 27 March 2017
                Publication date (Electronic): 23 May 2017
                Publication date Collection: June 2017
                Publication date PMC-release: 23 May 2017
                Volume: 85
                Issue: 6
                Electronic Location Identifier: e00969-16
                Affiliations
                Aeras, Rockville, Maryland, USA
                University of Florida
                Author notes
                Address correspondence to mbrennan@ 123456aeras.org .

                Citation Brennan MJ. 2017. The enigmatic PE/PPE multigene family of mycobacteria and tuberculosis vaccination. Infect Immun 85:e00969-16. https://doi.org/10.1128/IAI.00969-16.

                Article
                Publisher ID: 00969-16
                DOI: 10.1128/IAI.00969-16
                PMC ID: 5442627
                PubMed ID: 28348055
                SO-VID: fbac313f-b2bc-4b24-8342-fc86e307fce1
                Copyright © Copyright © 2017 Brennan.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 62, Pages: 8, Words: 6339
                Funding
                Funded by: Aeras Global Tuberculosis Vaccine Foundation (Aeras) https://doi.org/10.13039/100009342
                Categories
                Subject: Minireview
                Custom metadata
                cover-date June 2017

                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: tuberculosis,pe/ppe family of genes,vaccines
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: tuberculosis, pe/ppe family of genes, vaccines

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