The long-term objective of this project is to understand how the host immune system responds to the opportunistic protozoan parasite, Toxoplasma gondii, and to define the conditions under which immunity is effective and those under which it fails. This application specifically focuses on the role of neutrophils during T. gondii infection. It has recently been shown in mice that neutrophils are essential to survive acute toxoplasmosis, but the means by which they mediate protection are unclear. Polymorphonuclear leukocytes (PMN) are well known as one of the first components of the immune system to arrive at a focus of infection. The major function of these cells is conventionally thought to be microbicidal activity, mediated by phagocytosis and release of toxic molecules such as superoxide. However, a newly emerging view is that neutrophils are an important source of several important proinflammatory cytokines and chemokines. Our hypothesis is that PMN cytokine production accounts for their protective function, and that these cells are a crucial early IL- 12 source which triggers protective immunity to the parasite. There are four specific aims to evaluate this hypothesis. 1, Characterize the spectrum of cytokines and chemokines released by mouse neutrophils in response to T. gondii, and determine how the responses are modulated by exogenous cytokines. This will be accomplished using a combined approach of cytokine microarrays to examine upregulated gene transcription, and ELISA to examine protein expression. 2, Determine whether PMN serve as a source of cytokines, in particular IL-12, during infection initiated by intraperitoneal and oral inoculation. Confocal fluorescence microscopy, flow cytometry, and immunohistochemistry for intracellular cytokines will be employed to achieve this objective. 3, Determine if parasite-triggered neutrophil cytokines influence type 1 cytokine-based immunity.
This aim will be achieved examining the influence of neutrophils and their products on dendritic, T, and NK cell function. 4, Determine if neutrophils display toxoplasmastatic activity, and if such a response is influenced by exogenous cytokines. The ability of these cells to phagocytose tachyzoites will be evaluated using fluorescent endocytosis markers, and effects on parasite replication will be determined by uptake of 3H-UdR, a compound selectively incorporated by proliferating tachyzoites.
|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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