Many bacteria, viruses and parasites gain entry to their host in the intestine. While some pathogens remain in the mucosal environment, others disseminate to a variety of tissues where they may cause disease or establish chronic infections. Although it is widely accepted that CD8+ memory T cells are critical in controlling intracellular infections and often provide protection from reinfection, it is unclear how mucosal priming affects the quality and migration of these long-lived effector cells. Furthermore, it remains to be determined whether CD8+ memory cells can protect the mucosa from reinfection. The protozoan parasite Toxoplasma gondii is an excellent model organism with which to begin addressing these important questions. T. gondii is an orally transmitted parasite that initiates infection by invading cells in the intestinal environment, and later disseminates to multiple organs. In this proposal we outline in vivo experiments conducted in a natural rodent host to address the following fundamental question: How does intestinal infection influence CD8+ memory T cell development and function? T. gondii is highly amenable to genetic manipulation, therefore our experimental approach utilizes transgenic and knock-out parasites to address novel questions about the quality of CD8+ T cell memory following oral infection. Our experiments focus on two specific aims: First, we will utilize transgenic parasites and immunological assays to determine the quality of the CD8+ T cell memory response to mucosal versus systemic T. gondii infection. Second, we will employ adoptive transfer of CD8+ memory T cell subsets, in vivo antibody treatments and genetic manipulation of T. gondii to identify the mechanisms that protect the mucosa from reinfection. The basic questions outlined this proposal are central to the mission of the National Institute of Allergy and Infectious Disease (NIAID) to develop improved methods for preventing or treating disease. Furthermore, this proposal holds great interest for general public heath, as a more thorough understanding of the intestinal immune system has the potential to facilitate the development of oral vaccines that prevent disease by targeting pathogens at their point-of-entry in the gut. ? ? ?
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