This proposal will determine the potential for myeloid-derived suppressor cells (MDSC) as novel therapeutic targets against infection. MDSC have received a significant amount of recent attention for their well-defined immunosuppressive role in cancer. The response of MDSC in infection is not as well characterized as in cancer, but studies do show a consistent immunosuppressive phenotype associated with MDSC infiltration at sites of infection. In some infections, MDSC may have an early protective role. MDSC have the plasticity necessary to differentiate into inflammatory monocytes, macrophages, myeloid dendritic cells and neutrophils. Thus, the dual nature of the MDSC response (immunosuppressive or protective) may be due to the morphologic and biomarker heterogeneity of these cells, such that the balance of MDSC phenotypes and functions at any point during infection may determine the outcome. We have obtained preliminary data demonstrating a large response of MDSC in mice infected with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium). In addition, we have obtained preliminary evidence to suggest that while these cells may have an initial protective effect consistent with a role in innate immunity, they also have a potent inhibitory effect on T cells consistent with a role in suppression of adaptive immunity, which is a hallmark of S. Typhimurium infection. This application is built on the premise that MDSC can be targeted during infection in a temporal manner to capitalize on their protective role during the innate phase of the immune response and decrease their suppressive activity during the adaptive phase of the immune response.
In Specific Aim 1, we will characterize the response and role of MDSC in mice infected with S. Typhimurium. This will involve documenting whether S. Typhimurium-induced MDSC suppress T cell function through production of nitric oxide or arginase-1.
In Specific Aim 2, we will use a mouse model of infection with S. Typhimurium to determine if chemokine receptor CCR2 is required for emigration of MDSC out of bone marrow, and if MDSC can expand and mature in the periphery of mice infected with S. Typhimurium.
In Specific Aim 3, we will specifically target MDSC expansion, activation and suppressive activity at the transition from innate to adaptive immune response as a novel therapeutic approach to infection.
Microbial pathogens that infect humans have evolved the ability to co-opt or subvert the immune response as a strategy to promote disease. New therapeutic strategies that target the human immune response rather than the pathogen are needed to overcome the problem of increased human disease due to drug resistant microbial pathogens. This application will test the hypothesis that many pathogens co-opt immune cells to suppress protective responses, and that the co-opted immunosuppressive cells can be specifically targeted as a broad- spectrum therapeutic approach to block infectious diseases.
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