Sunday, November 24, 2024
11/24/2024
Project Summary/Abstract The long-term objective of this proposal is to understand inductive and effector mechanisms of host defense in the intestinal mucosa. We use as a tool the intracellular protozoan Toxoplasma gondii, an orally acquired opportunistic pathogen inducing strong protective Th1- and IFN--based immunity and that is a significant health hazard in immunocompromised populations. Signaling through the adaptor molecule MyD88 is necessary for optimal initiation of immunity and resistance to this pathogen. While IL-1 family cytokine receptors use MyD88, the primary role of this signaling adaptor during T. gondii infection is believed to be in Toll-like receptor (TLR) signaling. Nevertheless, the particular TLR involved (TLR11/12) are not expressed in humans and indeed many other species, indicating presence of MyD88-independent pathways of immune initiation. Such pathways are also present in mice, insofar as infection of MyD88 knockout animals triggers robust, albeit delayed, Th1 responses in the intestinal mucosa. Additionally, MyD88 knockout mice can be vaccinated against lethal challenge with orally inoculated Toxoplasma. Open questions remain regarding the role of MyD88 in specific cell types and in the context of the intestine how the microbiota influences MyD88-dependent and MyD88-independent immunity during Toxoplasma infection. The central hypothesis underpinning our research is that MyD88-dependent pathways and MyD88-independent pathways work together to provide optimal immune initiation during infection. We will address this hypothesis focusing on interactions between cells of the lamina propria, Toxoplasma and the host microbiota. Using our hypothesis to guide us, we will pursue three specific aims. Aim 1: Determine the role of intestinal epithelial cells in initiation of immunity and control of Toxoplasma. Using intestinal organoids we will examine how epithelial cells respond to infection, and how this impacts responses in the lamina propria compartment. The influence of epithelial MyD88 in immunity to T. gondii will be determined. Aim 2: Identify how MyD88 impacts innate lymphoid cell (ILC) function during Toxoplasma infection. The activity of ILC, with a focus on ILC1 and ILC3, will be examined using mouse strains deficient in ILC populations and strains with deletion of MyD88 in ILC. Aim 3: Determine the influence of MyD88 expression on generation of mucosal T cell effector and memory function. The requirement for MyD88 in lamina propria T cells will be determined with regard to short term effector function and long-term memory function. The importance of this research is that it will significantly extend and deepen our understanding of mechanisms of resistance to Toxoplasma within the mucosal immune system, which is critical to understanding mucosal host defense in humans. The ultimate impact of this research is that it can be expected to identify novel parasite and host targets for promoting resistance and immunity during infection with Toxoplasma and other microbial pathogens that threaten human health.
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