Hinterleitner & Dermody

i4Kids Pilot Grant FY21
Project Period: July 1, 2020 - December 31, 2021
Award Amount: $50,000

Celiac disease (CeD) is an important health problem mediated by ingestion of gluten found in wheat, barley, and rye. In CeD, genetically susceptible individuals expressing the human leukocyte antigen (HLA) DQ2 or DQ8 molecules display an inflammatory interferon-gamma (IFNg) T helper 1 (Th1) immune response to dietary gluten (Loss of oral tolerance to gluten, LOT). HLA-DQ2-or HLA-DQ8-restricted Th1 responses against gluten initiate CeD pathogenesis and precede development of villous atrophy. About 20% of children are at genetic risk for CeD development in the first three years of life, suggesting that LOT to gluten occurs in this window and that preventive strategies should be considered. With its high prevalence of 1-2% among the general population and the challenges of maintaining a gluten-free diet (GFD), the poor efficacy of a GFD in 40-60% of CeD patients, and the associated risks of other autoimmune diseases and cancer, CeD is a significant cause of disease and disability. There is considerable interest in defining new strategies to prevent and treat CeD in at-risk children. Intriguingly, although approximately 30% of the human population carry HLA DQ2 or DQ, only 1% develops CeD1, suggesting that additional genetic and environmental factors contribute to CeD pathogenesis. Viruses have been implicated in complex autoimmune and inflammatory disorders such as CeD and type1 diabetes. Reoviruses are nonenveloped viruses that contain a genome of 10 segments of double-stranded (ds) RNA. Enteric reovirus strain type 1 Lang (T1L) triggers inflammatory Th1 responses to dietary antigens, resulting in LOT and development of CeD. It is therefore of great interest to develop strategies that prevent virus-mediated inflammatory responses to dietary gluten. Commensal gut microbes have been suggested to influence oral tolerance. We have generated exciting data showing that the gut commensal protist Tritrichomonas (referred to as protist throughout this proposal) canprotectagainstT1L-mediated inflammatory Th1 responses to dietary antigens. We hypothesize that protists protect against virus-mediated LOT and that protist-based probiotics prevent LOT to gluten.