Role of CCL2/MCP-1 in mucosal immunity to Toxoplasma

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DESCRIPTION (provided by applicant): Toxoplasma gondii is a major AIDS-associated pathogen that can cause severe disease or death in congenitally infected infants. The parasite is also classified as an NIAID Category B priority microorganism. The long-term objective of this application is to understand the cellular immune response mechanisms that are necessary to control infection with this opportunistic protozoan pathogen, and to determine how dysfunctional responses can lead to immunopathology and inability to control infection. Preliminary data indicate that mice lacking expression of chemokine MCP-1 (CCL2) are highly susceptible to intraperitoneal infection with T. gondii, and this is associated with defective recruitment into the peritoneal cavity of a monocyte/dendritic cell- like population co-expressing Gr-1 and MHC class II and costimulatory molecules CD80/CD86 and CD40. Other recent studies have described similar cells, although whether they mediate protection or increase susceptibility is not clear and may depend upon the infection model. The goal of the present proposal is to determine whether cells double-positive for MHC class II and Gr-1 (MHC2+Gr-1+) are recruited during the mucosal immune response to oral infection with Toxoplasma. The specific aims we will employ to address this issue are as follows. 1, Determine the effects of CCL2 deficiency during oral infection compared to intraperitoneal infection, in particular whether the chemokine mediates resistance or susceptibility to Toxoplasma, and whether lack of CCL2 alters the Th1/Th2 balance during infection. 2, Determine if CCL2 recruits MHC2+GR-1+ cells during the mucosal immune response to infection. The ability of these cells to serve as an infection reservoir and to express microbicidal molecules and cytokines (in particular, IL-12) will also be examined. These aims will be achieved by ex vivo and in vitro analyses of cells isolated from intestinal mucosal tissues. Direct visualization of MHC class II-positive and Gr-1-positive cells in intestinal mucosa of wild-type and CCL2 negative mice will be accomplished by fluorescence immunohistochemistry. These studies can be expected to deepen our understanding of how immunity to Toxoplasma is initiated in mucosal tissues and will clarify the role of MHC2+Gr-1+ cells in this process. Understanding how immunity is triggered will ultimately lead to more effective means of controlling infection with Toxoplasma and other orally transmitted AIDS-associated microbial pathogens. The relevance of the project to public health is that Toxoplasma infects between 30-80% of the human population worldwide. While normally an asymptomatic infection, with suboptimal immune function the parasite emerges as a devastating and sometimes lethal infection. This project will enhance our understanding of immunity to the parasite, leading to improved treatment strategies.