: The long-term objective of this grant application is to understand the immune response mechanisms that are required to successfully control infection with the opportunistic protozoan Toxoplasma gondii, and how ineffective immunity contributes to pathogenesis of disease. The parasite is a major AIDS pathogen and can cause severe disease or death in congenitally infected infants. Toxoplasma induces potent Type 1 cytokine responses that are required in resistance to infection. This proposal focuses on the role of neutrophils in the mouse innate immune response to T. gondii infection. A hallmark characteristic of polymorphonuclear leukocytes (PMN) is their ability to rapidly accumulate in large numbers at foci of infection. Recent work by us and others has revealed an important immunoregulatory role for neutrophils in immune response ignition during microbial infection, and the overall goal of this proposal is to understand in molecular and cellular detail how neutrophils exert this immunoregulatory function.
An aim of this proposal is to characterize the role that PMN play in recruitment and activation of dendritic cells. This will be accomplished by examining how parasite-stimulated neutrophils influence dendritic cell activity both in vitro and in vivo.
A second aim i s to determine the extent to which cytokines and chemokines are present within PMN as preformed pools versus newly synthesized as a result of parasite stimulation, and to determine how exogenous cytokines control release of each cytokine pool. Another goal of this study is to initiate biochemical studies to define the role of MAPK and NFkappaB signaling pathways in control of neutrophil cytokine production during T. gondii stimulation. Finally, Toll-like receptors (TLR) have recently emerged as a major class of pattern recognition receptors involved in innate immune detection of microbial pathogens. The expression pattern of TLR on neutrophils and compared to dendritic cells will be examined. It will also be determined how TLR expression changes during stimulation with T. gondii antigen and during intracellular infection. These studies are expected to clarify how the immune response to Toxoplasma is initiated, and the function of neutrophils in this process. Understanding how immunity is triggered can be expected to lead to more effective means of controlling infection with Toxoplasma and other microbial pathogens.
|Abi Abdallah, Delbert S; Lin, Changyou; Ball, Carissa J et al. (2012) Toxoplasma gondii triggers release of human and mouse neutrophil extracellular traps. Infect Immun 80:768-77|
|Abi Abdallah, Delbert S; Egan, Charlotte E; Butcher, Barbara A et al. (2011) Mouse neutrophils are professional antigen-presenting cells programmed to instruct Th1 and Th17 T-cell differentiation. Int Immunol 23:317-26|
|Sukhumavasi, Woraporn; Warren, Amy L; Del Rio, Laura et al. (2010) Absence of mitogen-activated protein kinase family member c-Jun N-terminal kinase-2 enhances resistance to Toxoplasma gondii. Exp Parasitol 126:415-20|
|Denkers, Eric Y (2010) Toll-like receptor initiated host defense against Toxoplasma gondii. J Biomed Biotechnol 2010:737125|
|Egan, C E; Sukhumavasi, W; Butcher, B A et al. (2009) Functional aspects of Toll-like receptor/MyD88 signalling during protozoan infection: focus on Toxoplasma gondii. Clin Exp Immunol 156:17-24|
|Sukhumavasi, Woraporn; Egan, Charlotte E; Warren, Amy L et al. (2008) TLR adaptor MyD88 is essential for pathogen control during oral toxoplasma gondii infection but not adaptive immunity induced by a vaccine strain of the parasite. J Immunol 181:3464-73|
|Egan, Charlotte E; Sukhumavasi, Woraporn; Bierly, Allison L et al. (2008) Understanding the multiple functions of Gr-1(+) cell subpopulations during microbial infection. Immunol Res 40:35-48|
|Sukhumavasi, Woraporn; Egan, Charlotte E; Denkers, Eric Y (2007) Mouse neutrophils require JNK2 MAPK for Toxoplasma gondii-induced IL-12p40 and CCL2/MCP-1 release. J Immunol 179:3570-7|
|Bennouna, Soumaya; Sukhumavasi, Woraporn; Denkers, Eric Y (2006) Toxoplasma gondii inhibits toll-like receptor 4 ligand-induced mobilization of intracellular tumor necrosis factor alpha to the surface of mouse peritoneal neutrophils. Infect Immun 74:4274-81|
|Bennouna, Soumaya; Denkers, Eric Y (2005) Microbial antigen triggers rapid mobilization of TNF-alpha to the surface of mouse neutrophils transforming them into inducers of high-level dendritic cell TNF-alpha production. J Immunol 174:4845-51|
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