Enteric virus-induced innate immune responses in oral tolerance

The National Institute of Allergy and Infectious Diseases awarded the University of Pittsburgh $201,608 on June 12, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate how enteric viruses trigger loss of oral tolerance and inflammation.

The research examines how type 1 Lang (T1L) strain reovirus, a gut-infecting virus, initiates a specific form of cell death called necroptosis in intestinal epithelial cells, ultimately shifting dendritic cells toward inflammatory responses against dietary antigens such as gluten. The underlying mechanism involves viral production of Z-RNA, which activates the host protein ZBP1 to trigger necroptosis and inflammation. Aim 1 investigates how ZBP1 detects viral Z-RNA and induces necroptosis in intestinal epithelial cells. Aim 2 examines whether blocking or engaging the pathway can prevent or induce inflammatory dietary antigen-specific immune responses, with potential applications for preventing or treating autoimmune conditions and celiac disease.

Work is performed in Pittsburgh, Pennsylvania, with a performance period extending through May 31, 2028. The award is classified as a project grant, a standard assistance type under the program supporting biomedical research and research training in infectious diseases and related areas at nonprofit institutions.

Abstract

The human GUT must constantly balance between defending against harmful microbe, including virus infections, and tolerating harmless substances, like food. One important immune process called oral tolerance helps prevent the immune system from overreacting to dietary proteins such as gluten. When this tolerance breaks down, known as loss of oral tolerance (lot), IT can lead to celiac disease, where the body mounts an immune attack against gluten. Viruses that infect the GUT, known as enteric viruses, can disturb the intestinal immune homeostasis and contribute to gastrointestinal diseases. Our research has found that one such virus, the type 1 lang (T1L) strain of reovirus, capable of infecting human and mice, can induce lot to gluten. We discovered that T1L triggers a type of inflammatory cell death called necroptosis in intestinal epithelial cells. This cell death sends danger signals to dendritic cells (DCS) presenting dietary antigens, including gluten to T cells. These signals appear to shift DCS from a tolerance-promoting mode to one that drives inflammation and gluten-specific TH1 responses, a hallmark of celiac disease. We believe this process begins when the virus produces a specific form of RNA called Z-RNA, which is sensed by a host protein called ZBP1, triggering necroptosis and inflammation. Our research aims to understand this pathway in detail. Aim 1 will investigate how ZBP1 detects viral Z-RNA and induces necroptosis in intestinal epithelial cells. Aim 2 will examine how this necroptosis leads to lot and will test whether blocking or engaging the pathway can prevent or induce inflammatory dietary antigen-specific TH1 immune responses. By revealing how a common virus can break oral tolerance and trigger inflammation, this study could lead to new ways to prevent or treat autoimmune and food-related disease such as celiac disease.