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METAPATH Report Summary

Project ID: 625328
Funded under: FP7-PEOPLE
Country: France

Final Report Summary - METAPATH (Integrated study of skin resident Memory T cells and dermal mononuclear phagocytes in the fight against PATHogens)

Staphylococcus aureus (SA) infections represent a major threat for public health. Indeed, SA is responsible for the vast majority of bacterial skin infections in humans and is associated with considerable morbidity and mortality. Unlike typical encapsulated bacterial pathogens, which induce efficient protective humoral immune responses, there is no clear evidence that antibody responses are sufficient to protect against SA. This could explain why humoral vaccine strategies were unsuccessful with SA. In contrast, there is increasing evidence that IL-17-producing T cells provide cell-mediated immunity against SA but it is unknown whether these T cells representαβor γδ T cells. Moreover, recent studies showed that the skin immune system relied on its resident microbiota to mount a protective response against skin pathogens. In healthy individuals, bacteria belonging to the Staphylococcus species are commensal that colonize body surfaces such as the nares and the skin.
In the frame of the MetaPATH project, I studied the importance of skin colonization with Staphylococcus aureus (SA) on the immune response against SA. I found that the immune response against SA was modulated by the commensal flora as skin colonization of adult mice by SA allows faster clearance of SA subsequently inoculated in the dermis and abrogates its spread to the draining lymph nodes (LNs). Using state-of-the-art flow cytometry analysis of both the innate and adaptive compartments of the immune response including the neutrophils, myeloid cells, αβ and γδ T cells, I could associate a specific immune signature with the protective immunity against SA. Moreover, I showed that skin colonization induced a long term protective memory as mice colonized with SA 2 month earlier were still protected from SA translocation to the LNs following intradermal infection with SA and found that a single topical application of SA was enough to induce protective immunity against SA infection. As neutrophils were described to play a key role in bacterial clearance, we decided to assess their role in our SA colonization/infection model. We thus used the genista mouse model which are deficient for Ly6Ghi neutrophils. We then showed that the absence of Ly6Ghi neutrophils did not impair the innate and adaptive T cell responses and that neutrophils are not key players to protect the mouse from SA translocation to the LNs following intradermal infection with SA.
The dermal dendritic cells (DCs) have an important role in recognizing, processing and conveying foreign material from the periphery such as the skin to the draining lymph nodes where they can activate naïve T cells. The outcome of adaptive immune responses depends in large part from the quality of the interactions between T cells and DCs. Using bone marrow chimeras in which the migration of a specific DC subset is impaired allowed us to show that part of the adaptive immune response, found in animals that were pre-colonized with SA, was impaired whereas the animals were still protected from SA translocation to the LNs following intradermal infection with SA. This study brought lights on the role of this specific migratory DC subset in the induction of adaptive immune response against SA. Moreover, in this bone marrow chimera model, the γδ T cells innate response was untouched suggesting a key role of these cells in our SA model at least for the short term memory.
In the frame of the IOF MetaPATH project, we made major progress on the understanding of the immune mechanisms associated with skin colonization with SA and protection against SA skin infection. All those results will now be taken in account to design vaccine strategies against Staphylococcus aureus.

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