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.
|Caballero, Silvia; Kim, Sohn; Carter, Rebecca A et al. (2017) Cooperating Commensals Restore Colonization Resistance to Vancomycin-Resistant Enterococcus faecium. Cell Host Microbe 21:592-602.e4|
|Xiong, Huizhong; Keith, James W; Samilo, Dane W et al. (2016) Innate Lymphocyte/Ly6C(hi) Monocyte Crosstalk Promotes Klebsiella Pneumoniae Clearance. Cell 165:679-89|
|Xiong, Huizhong; Carter, Rebecca A; Leiner, Ingrid M et al. (2015) Distinct Contributions of Neutrophils and CCR2+ Monocytes to Pulmonary Clearance of Different Klebsiella pneumoniae Strains. Infect Immun 83:3418-27|
|Xiong, Huizhong; Pamer, Eric G (2015) Monocytes and infection: modulator, messenger and effector. Immunobiology 220:210-4|
|Franklin, Ruth A; Liao, Will; Sarkar, Abira et al. (2014) The cellular and molecular origin of tumor-associated macrophages. Science 344:921-5|
|Ryder, Mabel; Gild, Matti; Hohl, Tobias M et al. (2013) Genetic and pharmacological targeting of CSF-1/CSF-1R inhibits tumor-associated macrophages and impairs BRAF-induced thyroid cancer progression. PLoS One 8:e54302|
|Samstein, Miriam; Schreiber, Heidi A; Leiner, Ingrid M et al. (2013) Essential yet limited role for CCR2? inflammatory monocytes during Mycobacterium tuberculosis-specific T cell priming. Elife 2:e01086|
|van Heijst, Jeroen W J; Ceberio, Izaskun; Lipuma, Lauren B et al. (2013) Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation. Nat Med 19:372-7|
|Kinnebrew, Melissa A; Buffie, Charlie G; Diehl, Gretchen E et al. (2012) Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36:276-87|
|Serbina, Natalya V; Shi, Chao; Pamer, Eric G (2012) Monocyte-mediated immune defense against murine Listeria monocytogenes infection. Adv Immunol 113:119-34|
Showing the most recent 10 out of 32 publications