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      Staphylococcus aureus Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin

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          Abstract

          Antigen-presenting cells such as dendritic cells (DCs) fulfill an indispensable role in the development of adaptive immunity by producing proinflammatory cytokines and presenting microbial antigens to lymphocytes to trigger a faster, specific, and long-lasting immune response. Here, we studied the effect of Staphylococcus aureus toxins on human DCs. We discovered that the leukocidin LukAB hinders the development of adaptive immunity by targeting human DCs. The ability of S. aureus to blunt the function of DCs could help explain the high frequency of recurrent S. aureus infections. Taken together, the results from this study suggest that therapeutically targeting the S. aureus leukocidins may boost effective innate and adaptive immune responses by protecting innate leukocytes, enabling proper antigen presentation and T cell activation.

          ABSTRACT

          Staphylococcus aureus is a human pathogen responsible for high morbidity and mortality worldwide. Recurrent infections with this bacterium are common, suggesting that S. aureus thwarts the development of sterilizing immunity. S. aureus strains that cause disease in humans produce up to five different bicomponent toxins (leukocidins) that target and lyse neutrophils, innate immune cells that represent the first line of defense against S. aureus infections. However, little is known about the role of leukocidins in blunting adaptive immunity. Here, we explored the effects of leukocidins on human dendritic cells (DCs), antigen-presenting cells required for the development of adaptive immunity. Using an ex vivo infection model of primary human monocyte-derived dendritic cells, we found that S. aureus, including strains from different clonal complexes and drug resistance profiles, effectively kills DCs despite efficient phagocytosis. Although all purified leukocidins could kill DCs, infections with live bacteria revealed that S. aureus targets and kills DCs primarily via the activity of leukocidin LukAB. Moreover, using coculture experiments performed with DCs and autologous CD4 + T lymphocytes, we found that LukAB inhibits DC-mediated activation and proliferation of primary human T cells. Taken together, the data determined in the study reveal a novel immunosuppressive strategy of S. aureus whereby the bacterium blunts the development of adaptive immunity via LukAB-mediated injury of DCs.

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          Most cited references 71

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          Staphylococcus aureus infections.

           Franklin Lowy (1998)
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            Waves of resistance: Staphylococcus aureus in the antibiotic era.

            Staphylococcus aureus is notorious for its ability to become resistant to antibiotics. Infections that are caused by antibiotic-resistant strains often occur in epidemic waves that are initiated by one or a few successful clones. Methicillin-resistant S. aureus (MRSA) features prominently in these epidemics. Historically associated with hospitals and other health care settings, MRSA has now emerged as a widespread cause of community infections. Community or community-associated MRSA (CA-MRSA) can spread rapidly among healthy individuals. Outbreaks of CA-MRSA infections have been reported worldwide, and CA-MRSA strains are now epidemic in the United States. Here, we review the molecular epidemiology of the epidemic waves of penicillin- and methicillin-resistant strains of S. aureus that have occurred since 1940, with a focus on the clinical and molecular epidemiology of CA-MRSA.
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              Trained immunity: A program of innate immune memory in health and disease.

              The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity, as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed "trained immunity" or "innate immune memory." Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, new therapeutic strategies for the treatment of immune deficiency states, and modulation of exaggerated inflammation in autoinflammatory diseases.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                mBio
                MBio
                mbio
                mbio
                mBio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                2 January 2019
                Jan-Feb 2019
                : 10
                : 1
                Affiliations
                [a ]Department of Microbiology, New York University School of Medicine, New York, New York, USA
                [b ]Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York, USA
                [c ]Microscopy Laboratory, Division of Advanced Research Technologies, New York University School of Medicine, New York, New York, USA
                [d ]Department of Medicine, Division of Infectious Diseases, New York University School of Medicine, New York, New York, USA
                University of Illinois at Chicago
                Author notes
                Address correspondence to Victor J. Torres, Victor.Torres@ 123456nyumc.org .
                [*]

                Present address: Mickaël M. Ménager, INSERM UMR1163, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Paris, France.

                E.T.M.B., X.Z., and E.E.Z. contributed equally to this article.

                Article
                mBio01918-18
                10.1128/mBio.01918-18
                6315100
                30602580
                Copyright © 2019 Berends et al.

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

                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 71, Pages: 16, Words: 10091
                Product
                Funding
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
                Award ID: AI099394
                Award Recipient :
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
                Award ID: AI105129
                Award Recipient :
                Categories
                Research Article
                Host-Microbe Biology
                Editor's Pick
                Custom metadata
                January/February 2019

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