Food and waterborne protozoan infections are a common cause of severe human disease worldwide, including in the United States. Infection with the parasite Toxoplasma gondii occurs by an oral route following ingestion of oocysts contaminating the environment or of tissue cysts found in meat of infected animals. Parasite infection of intestinal epithelial cells results in inflammatory changes that recruit new populations of cells and activate the innate immune response. Resident dendritic cells (DC) in the gut are likely key mediators of the initial response; however their role in oral toxoplasmosis has not been characterized previously. Our recent studies have shown that newly recruited, inflammatory monocytes are also important for control of toxoplasmosis in the murine model. The proposed studies will utilize oral infection with T. gondii in the mouse as a model to delineate innate immune responses in the mucosa that are important for control of enteric infections. The proposed studies test the hypothesis that recruitment of inflammatory monocytes is responsible for induction of innate mucosal immunity and control of oral toxoplasmosis. We will define the roles of dendritic cells (DC) and inflammatory monocytes in the production of cytokines/chemokines that result in cellular recruitment and activation in the gut following infection with T. gondii. We will also examine the functions of resident and recruited myeloid cells in generating microbicidal responses that lead to the control of T. gondii infection. Finally, we will test the role of specific subsets of myeloid cells in control of T. gondii infection in the gut using transgenic mice with altered expression of chemokines or cellular receptors necessary for signaling. These studies will define the role of DC and monocytes in innate immune responses in the gut during acute toxoplasmosis. The findings will have important implications for future studies to characterize mechanisms of microbial killing, to define factors that result in polarization of protective responses, and in the design of vaccines to protect against protozoan and possibly other enteric pathogens. ? ? ?
| Dunay, Ildiko R; Sibley, L David (2010) Monocytes mediate mucosal immunity to Toxoplasma gondii. Curr Opin Immunol 22:461-6 |
| Dunay, Ildiko R; Fuchs, Anja; Sibley, L David (2010) Inflammatory monocytes but not neutrophils are necessary to control infection with Toxoplasma gondii in mice. Infect Immun 78:1564-70 |
| Dunay, Ildiko R; Chan, Wing Chi; Haynes, Richard K et al. (2009) Artemisone and artemiside control acute and reactivated toxoplasmosis in a murine model. Antimicrob Agents Chemother 53:4450-6 |
| Dunay, Ildiko R; Damatta, Renato A; Fux, Blima et al. (2008) Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity 29:306-17 |
| Zhao, Zijiang; Fux, Blima; Goodwin, Megan et al. (2008) Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell Host Microbe 4:458-69 |
