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      Bacteria Modulate the CD8+ T Cell Epitope Repertoire of Host Cytosol-Exposed Proteins to Manipulate the Host Immune Response

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      PLoS Computational Biology
      Public Library of Science

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          Abstract

          The main adaptive immune response to bacteria is mediated by B cells and CD4+ T-cells. However, some bacterial proteins reach the cytosol of host cells and are exposed to the host CD8+ T-cells response. Both gram-negative and gram-positive bacteria can translocate proteins to the cytosol through type III and IV secretion and ESX-1 systems, respectively. The translocated proteins are often essential for the bacterium survival. Once injected, these proteins can be degraded and presented on MHC-I molecules to CD8+ T-cells. The CD8+ T-cells, in turn, can induce cell death and destroy the bacteria's habitat. In viruses, escape mutations arise to avoid this detection. The accumulation of escape mutations in bacteria has never been systematically studied. We show for the first time that such mutations are systematically present in most bacteria tested. We combine multiple bioinformatic algorithms to compute CD8+ T-cell epitope libraries of bacteria with secretion systems that translocate proteins to the host cytosol. In all bacteria tested, proteins not translocated to the cytosol show no escape mutations in their CD8+ T-cell epitopes. However, proteins translocated to the cytosol show clear escape mutations and have low epitope densities for most tested HLA alleles. The low epitope densities suggest that bacteria, like viruses, are evolutionarily selected to ensure their survival in the presence of CD8+ T-cells. In contrast with most other translocated proteins examined, Pseudomonas aeruginosa's ExoU, which ultimately induces host cell death, was found to have high epitope density. This finding suggests a novel mechanism for the manipulation of CD8+ T-cells by pathogens. The ExoU effector may have evolved to maintain high epitope density enabling it to efficiently induce CD8+ T-cell mediated cell death. These results were tested using multiple epitope prediction algorithms, and were found to be consistent for most proteins tested.

          Author Summary

          Bacterial proteins are mainly exposed to B-cells and CD4+ T-cells, while CD8+ T-cells (CTL) typically respond to viruses. The limitation of the CTL response to viruses results from processing pathways of epitopes presented to CTLs. These epitopes usually stem from proteins expressed in the cytosol. Such proteins are eventually degraded and presented on MHC-I molecules to CTLs. However bacterial Type III secretion system (T3SS) effectors also have an access to the host cytosol and may also be exposed to CTL response. Thus, we can assume that this group of proteins undergoes selection against the presentation of CTL epitopes, as seen in viral proteins. Using multiple epitope prediction algorithms, we show that most T3SS effectors, as well as LLO, and ActA in Listeria monocytogenes and ESAT-6 proteins in Mycobacterium tuberculosis, are systematically selected to reduce the number and quality of their epitopes. The exception in this respect is the Pseudomonas aeruginosa effector ExoU that has high density of high quality epitopes. Since ExoU is known to induce rapid cell death in hosts cells, we assume that P.aeruginosa utilize the immune response to induce such death. The E.coli epitope density is highly variable among strains.

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          Most cited references80

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          Enteropathogenic E. coli (EPEC) transfers its receptor for intimate adherence into mammalian cells.

          Enteropathogenic E. coli (EPEC) belongs to a group of bacterial pathogens that induce epithelial cell actin rearrangements resulting in pedestal formation beneath adherent bacteria. This requires the secretion of specific virulence proteins needed for signal transduction and intimate adherence. EPEC interaction induces tyrosine phosphorylation of a protein in the host membrane, Hp90, which is the receptor for the EPEC outer membrane protein, intimin. Hp90-intimin interaction is essential for intimate attachment and pedestal formation. Here, we demonstrate that Hp90 is actually a bacterial protein (Tir). Thus, this bacterial pathogen inserts its own receptor into mammalian cell surfaces, to which it then adheres to trigger additional host signaling events and actin nucleation. It is also tyrosine-phosphorylated upon transfer into the host cell.
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            Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains.

            A method to predict the relative binding strengths of all possible nonapeptides to the MHC class I molecule HLA-A2 has been developed based on experimental peptide binding data. These data indicate that, for most peptides, each side-chain of the peptide contributes a certain amount to the stability of the HLA-A2 complex that is independent of the sequence of the peptide. To quantify these contributions, the binding data from a set of 154 peptides were combined together to generate a table containing 180 coefficients (20 amino acids x 9 positions), each of which represents the contribution of one particular amino acid residue at a specified position within the peptide to binding to HLA-A2. Eighty peptides formed stable HLA-A2 complexes, as assessed by measuring the rate of dissociation of beta 2m. The remaining 74 peptides formed complexes that had a half-life of beta 2m dissociation of less than 5 min at 37 degrees C, or did not bind to HLA-A2, and were included because they could be used to constrain the values of some of the coefficients. The "theoretical" binding stability (calculated by multiplying together the corresponding coefficients) matched the experimental binding stability to within a factor of 5. The coefficients were then used to calculate the theoretical binding stability for all the previously identified self or antigenic nonamer peptides known to bind to HLA-A2. The binding stability for all other nonamer peptides that could be generated from the proteins from which these peptides were derived was also predicted. In every case, the previously described HLA-A2 binding peptides were ranked in the top 2% of all possible nonamers for each source protein. Therefore, most biologically relevant nonamer peptides should be identifiable using the table of coefficients. We conclude that the side-chains of most nonamer peptides to the first approximation bind independently of one another to the HLA-A2 molecule.
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              MHC class I antigen presentation: learning from viral evasion strategies.

              The cell surface display of peptides by MHC class I molecules to lymphocytes provides the host with an important surveillance mechanism to protect against invading pathogens. However, in turn, viruses have evolved elegant strategies to inhibit various stages of the MHC class I antigen presentation pathway and prevent the display of viral peptides. This Review highlights how the elucidation of mechanisms of viral immune evasion is important for advancing our understanding of virus-host interactions and can further our knowledge of the MHC class I presentation pathway as well as other cellular pathways.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                1553-734X
                1553-7358
                October 2011
                October 2011
                13 October 2011
                : 7
                : 10
                : e1002220
                Affiliations
                [1 ]Department of Mathematics and Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel
                [2 ]Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                La Jolla Institute for Allergy and Immunology, United States of America
                Author notes

                Conceived and designed the experiments: YM YL. Performed the experiments: YM YL. Analyzed the data: YM RNP YL. Contributed reagents/materials/analysis tools: YM RNP YL. Wrote the paper: YM YL.

                Article
                PCOMPBIOL-D-11-00140
                10.1371/journal.pcbi.1002220
                3192822
                22022257
                bdd6fbb6-dd25-44e2-b08e-03c38b6e61a1
                Maman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 1 February 2011
                : 20 August 2011
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Evolutionary Biology
                Immunology
                Computer Science
                Algorithms

                Quantitative & Systems biology
                Quantitative & Systems biology

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