Control of infection with intracellular pathogens depends on the ability of the innate immune response to limit microbial replication and injury in the initial days of infection and then to efficiently facilitate the development of adaptive (antigen-specific) immunity. The innate immune system has an inherent ability to discriminate between microbial pathogens and self, a function fulfilled in part by toll-like receptors (TLRs). In addition to their important role in activating innate defenses, TLRs are thought to play an essential role in the activation of dendritic cells (DCs), which link innate and adaptive immunity, influencing the quality and magnitude of the antigen-specific immune response and the outcome of the infection. Interferon-gamma (IFN-gamma)-producing Th1 CD4+T cells and cytotoxic CD8+T cells are key components of protective antigen-specific immunity to intracellular pathogens. This proposal addresses the role of TLRs in innate immunity and in the activation of DCs leading to the induction of antigen-specific immunity to the intracellular bacterial pathogen, Listeria monocytogenes (Lm), and the mechanisms by which IFN-gamma is regulated in the context of this infection. Lm is a food-borne pathogen that causes severe disease in the fetus and newborn infant, and the murine model of Lm infection provides a robust system in which to address mechanisms linking innate and adaptive immunity in adults and neonates.
Aim 1. Determine which TLRs contribute and the cumulative role of TLRs in the innate immune response to Lm.
Aim 2. Determine the cumulative role of TLRs and MyD88 in activating DCs and in linking innate to adaptive immunity to Lm.
Aim 3. Determine whether deficits in TLR/Myd88-dependent or -independent mechanisms impair the development of T cell-mediated immunity to and protection from Lm in the neonate.
Aim 4. Determine the importance of conserved non-coding sequences (CSE1/2) in proper expression of IFN-gamma in the context of the immune response to Lm. These studies will provide insights into mechanisms for host defense against Lm and for the greater susceptibility of the neonate to this and related intracellular bacterial pathogens.
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