Friday, April 19, 2024
4/19/2024
PROJECT SUMMARY The intestinal lumen hosts a numerous and diverse body of microbes such as bacteria, fungi, and viruses, creating a stimuli-rich environment. A single layer of epithelial cells separates the lumen from the mucosal immune system, which is the most populous immune cell reservoir in the body. The proximity of the mucosal immune system to the intestinal barrier positions it as a first responder to noxious infections. The immune system at the mucosa must not only be able to recognize and respond to pathogens in a controlled manner, but also tolerate harmless stimuli. Dysregulation of both microbial communities and the mucosal immune response can lead to diseases such as allergies, inflammatory bowel disease (IBD) and colorectal cancer. Thus, it is crucial to understand the crosstalk between infection and the immune response in order to develop therapeutics against such diseases. Despite their prevalence, the effect of intestinal viruses on the host are not well understood. Human noroviruses, which are single stranded RNA viruses, can establish persistent enteric infection and cause viral gastroenteritis. Murine norovirus (MNV) is a related virus that naturally infects mice, and thus allows for the use of mouse models to study mucosal immunity during persistent viral infections. The CR6 strain of MNV establishes a chronic intestinal infection, particularly in tuft cells which are rare secretory epithelial cells. MNV infection can have both beneficial and harmful effects. In part mediated by type I interferon signaling, MNV protects microbiota-depleted mice from chemically induced colitis. However, in mouse models of IBD, MNV exacerbates intestinal inflammation and morbidity. This noxious effect is ascribed to increased cytokine production by CD8-expressing intraepithelial lymphocytes (IELs). IELs are a diverse and abundant T cell population residing at the intestinal epithelium. Similar to the contrasting effects of MNV in different contexts, tissue surveillance, pro- and anti- inflammatory roles have been ascribed to various IEL subsets. However, the mechanisms underlying IEL development and function and poorly characterized. The goal of this proposal is to elucidate the impact of persistent enteric viral infection on CD8-expressing intraepithelial lymphocytes (CD8-IELs). We will utilize MNV-CR6, which naturally establishes a chronic intestinal infection in mice and affects local CD8 T cells, to study the host immune response. We aim to elucidate the functional mechanisms involved in CD8-IELs responding to MNV and define their fate upon response.
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