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      PSM Peptides From Community-Associated Methicillin-Resistant Staphylococcus aureus Impair the Adaptive Immune Response via Modulation of Dendritic Cell Subsets in vivo

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          Dendritic cells (DCs) are key players of the immune system and thus a target for immune evasion by pathogens. We recently showed that the virulence factors phenol-soluble-modulins (PSMs) produced by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains induce tolerogenic DCs upon Toll-like receptor activation via the p38-CREB-IL-10 pathway in vitro. Here, we addressed the hypothesis that S. aureus PSMs disturb the adaptive immune response via modulation of DC subsets in vivo. Using a systemic mouse infection model we found that S. aureus reduced the numbers of splenic DC subsets, mainly CD4 + and CD8 + DCs independently of PSM secretion. S. aureus infection induced upregulation of the C-C motif chemokine receptor 7 (CCR7) on the surface of all DC subsets, on CD4 + DCs in a PSM-dependent manner, together with increased expression of MHCII, CD86, CD80, CD40, and the co-inhibitory molecule PD-L2, with only minor effects of PSMs. Moreover, PSMs increased IL-10 production in the spleen and impaired TNF production by CD4 + DCs. Besides, S. aureus PSMs reduced the number of CD4 + T cells in the spleen, whereas CD4 +CD25 +Foxp3 + regulatory T cells (T regs) were increased. In contrast, Th1 and Th17 priming and IFN-γ production by CD8 + T cells were impaired by S. aureus PSMs. Thus, PSMs from highly virulent S. aureus strains modulate the adaptive immune response in the direction of tolerance by affecting DC functions.

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          Most cited references 39

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          Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA.

          Methicillin-resistant Staphylococcus aureus (MRSA) remains a major human pathogen. Traditionally, MRSA infections occurred exclusively in hospitals and were limited to immunocompromised patients or individuals with predisposing risk factors. However, recently there has been an alarming epidemic caused by community-associated (CA)-MRSA strains, which can cause severe infections that can result in necrotizing fasciitis or even death in otherwise healthy adults outside of healthcare settings. In the US, CA-MRSA is now the cause of the majority of infections that result in trips to the emergency room. It is unclear what makes CA-MRSA strains more successful in causing human disease compared with their hospital-associated counterparts. Here we describe a class of secreted staphylococcal peptides that have a remarkable ability to recruit, activate and subsequently lyse human neutrophils, thus eliminating the main cellular defense against S. aureus infection. These peptides are produced at high concentrations by standard CA-MRSA strains and contribute significantly to the strains' ability to cause disease in animal models of infection. Our study reveals a previously uncharacterized set of S. aureus virulence factors that account at least in part for the enhanced virulence of CA-MRSA.
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            Staphylococcal manipulation of host immune responses.

            Staphylococcus aureus, a bacterial commensal of the human nares and skin, is a frequent cause of soft tissue and bloodstream infections. A hallmark of staphylococcal infections is their frequent recurrence, even when treated with antibiotics and surgical intervention, which demonstrates the bacterium's ability to manipulate innate and adaptive immune responses. In this Review, we highlight how S. aureus virulence factors inhibit complement activation, block and destroy phagocytic cells and modify host B cell and T cell responses, and we discuss how these insights might be useful for the development of novel therapies against infections with antibiotic resistant strains such as methicillin-resistant S. aureus.
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              CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen.

              The dendritic cells (DC) of mouse spleen and thymus were examined for expression of CD4 and CD8. Provided care was taken to avoid selective extraction or selective depletion of DC subpopulations, three main types of DC were detected in mouse spleen: a major new population of CD4+8- DEC-205low CD11bhigh DC, together with the previously described CD4-8- DEC-205low CD11bhigh DC and CD4-8alphaalpha+ DEC-205high CD11blow DC. The CD4 on the surface of the CD4+ splenic DC subpopulation was produced by the DC themselves, and CD4 RNA transcripts were present. Likewise, the CD8alpha on the surface of the splenic CD8+ DC was shown to be a product of the DC themselves, in agreement with earlier evidence. All three spleen DC types would be considered as mature, based on expression of CD80, CD86, and CD40 as well as on T cell stimulating function. Mouse thymuses appeared to contain two DC types; both were DEC-205highCD11blow, but they differed in the level of CD8alphaalpha expression. However, as well as this authenticated marker expression, immunofluorescent staining was also found to reflect a series of artifacts, due to the autofluorescence of contaminating cells and due to pickup of CD4 and CD8alphabeta. By constructing mice chimeric for the hemopoietic lineages using mixtures of wild-type bone marrow with CD4null or CD8alphanull bone marrow, a marked pickup by thymic DC of Ags derived from thymocytes was demonstrated.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                10 May 2019
                : 10
                1Department of Internal Medicine II, University of Tübingen , Tübingen, Germany
                2Quantitative Biology Center, University of Tübingen , Tübingen, Germany
                Author notes

                Edited by: Joseph Alex Duncan, University of North Carolina at Chapel Hill, United States

                Reviewed by: Rebecca Leigh Schmidt, Upper Iowa University, United States; Frank Verreck, Biomedical Primate Research Centre, Netherlands

                *Correspondence: Stella E. Autenrieth stella.autenrieth@

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                Copyright © 2019 Richardson, Armbruster, Günter, Biljecki, Klenk, Heumos and Autenrieth.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 48, Pages: 12, Words: 6950
                Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659
                Funded by: European Social Fund 10.13039/501100004895
                Original Research


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