Role of inflammatory monocytes in immunity and host defense against Salmonella

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PROJECT SUMMARY Inflammatory monocytes are innate immune cells that play a key role in immunity and host defense. They originate from progenitors in bone marrow and, under certain pathological conditions, can be recruited from bone marrow into tissues. Inflammatory monocytes resemble mononuclear myeloid-derived suppressor cells, which have been associated with immunosuppression in cancer and, more recently infection; yet their role in host immune responses to bacterial triggers is not well understood. To address this knowledge gap, we have been investigating the role of inflammatory monocytes in the host immune response to Salmonella, which are pathogenic bacteria that cause significant morbidity and mortality in humans worldwide. We have published that inflammatory monocytes purified from tissues of mice infected with Salmonella exhibit both protective and immunosuppressive properties that may influence the outcome of the infection. Furthermore, we have published that inflammatory monocytes provide a niche for Salmonella expansion in the lumen of the inflamed intestine. Recent work from our laboratory described in this application has indicated that inflammatory monocytes play an essential role in both early and late control of persistent Salmonella infection. Collectively, these published and unpublished findings establish that inflammatory monocytes play a key role in the host immune response to Salmonella. The objective of this application is to define how inflammatory monocytes modulate host interactions with Salmonella, a high impact topic important for understanding the role of inflammatory monocytes in immunity and host defense. Our central hypothesis is that inflammatory monocytes play a key role not only in the induced innate immune response to Salmonella, but also in directing the course of the adaptive immune response to Salmonella. To test various aspects of our central hypothesis and accomplish our objective, we will 1) define how inflammatory monocytes contribute to the pathogenesis of Salmonella-induced colitis and 2) define how inflammatory monocytes help control persistent Salmonella infection. Conceptual advances resulting from the proposed research are expected to provide new, fundamental insights into the role of inflammatory monocytes in immunity and host defense, and thus will have a strong and sustained influence on the field.