Innate immune defense against intracellular pathogens depends upon recruitment of circulating monocytes to sites of infection. The CCR2+ monocyte subset plays a particularly important role in defense against the intracellular bacterial pathogen Listeria monocytogenes. Our studies have demonstrated that CCR2, a chemokine receptor that binds three distinct chemokines, MCP-1 (CCL2), MCP-3 (CCL7) and MCP-5 (CCL12), is essential for the emigration of CCR2+ monocytes from bone marrow during infection. The goal of the proposed studies is to obtain a comprehensive understanding of monocyte recruitment and activation during the innate immune response to L. monocytogenes infection.
Our first aim i s to determine the relative contributions of MCP-1, MCP-3 and MCP-5 to CCR2+ monocyte recruitment. We will use mice with genetic deletions of each of these chemokines to determine susceptibility to infection and to characterize monocyte recruitment in vivo. In addition, we will use transgenic MCP-reporter mice to determine which cells are producing chemokines in vivo.
The second aim i s to investigate the association of MCP chemokines with tissues such as spleen, liver and bone marrow during bacterial infection. We will generate tagged and radiolabeled MCPs and measure their in vivo localization during bacterial infection.
Our third aim will investigate in vivo mechanisms that promote CCR2+ monocyte emigration from bone marrow and immigration into infected tissues. We will generate a transgenic reporter mouse that will enable in vivo tracking of CCR2+ monocytes in bone marrow and infected tissues. These studies will provide a novel view of monocyte recruitment during infection and are likely to provide a platform for the development of therapeutic strategies to enhance innate immune defense against conventional and biodefense-related pathogens. ? ? ?
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