Celiac disease (CD) is an immune-mediated enteropathy that occurs in a subset of genetically predisposed individuals exposed to gluten. While approximately 30-45% of the U.S. population carries the risk alleles, only 1% of the population develops the disease. This finding suggests that other genetic and environmental factors are required for CD development. Viral infections are associated with the induction of many autoimmune and inflammatory diseases. Accordingly, several viruses have been implicated in the onset of CD. However, not all viruses confer disease susceptibility, and little i known about specific viral determinants that mediate immunopathologic outcomes. Viruses of the Reoviridae family have been linked to CD in prospective human studies. Peroral (PO) inoculation of mice with reovirus strain T1L abrogates oral tolerance to ovalbumin (OVA), as marked by an increase in OVA-specific T cell proliferation and inflammatory cytokine production in the draining lymph node following antigen restimulation. However, mice inoculated with strain T3D-RV develop normal immunological tolerance to OVA, indicated by an increase in regulatory T cells. Both virus strains produce comparable titers in the intestine, Peyer's Patches, mesenteric lymph nodes, and spleen at 24 hours after PO inoculation. In a preliminary experiment using CD-prone HLA-DQ8 mice, T1L also abrogates oral tolerance to gluten and leads to CD-like pathology. These findings indicate that reovirus infection alters immunologic responses to fed antigen, similar to the immunopathology of CD, in a strain-specific manner. Based on this information, three integrated specific aims are proposed to enhance an understanding of mechanisms of virus-induced loss of oral tolerance (LOT) to fed antigen.
In Specific Aim 1, I will identify viral gene segments required for LOT and determine how these segments alter virus-host interactions during tolerance abrogation. We have constructed eight reassortant viruses that segregate the eight genes that differ between T1L and T3D-RV. Mice will be infected with T1L, T3D-RV, and each of the T1L x T3D-RV reassortants to identify the genetic basis of strain-specific differences in LOT, viral tropism, and immune responses.
In Specific Aim 2, I will elucidate mechanisms by which reovirus induces LOT. Once key viral genes have been identified, viral protein domains required for LOT will be defined by reciprocally exchanging sequences between alleles associated with LOT (risk alleles) and those that are not (protective alleles). The resultant viruses will be compared to T1L and T3D-RV for effects on LOT and virus-host interactions.
In Specific Aim 3, I will determine mechanisms by which reovirus infection induces CD-like pathology in mice. HLA-DQ8 transgenic mice will be infected with reovirus T1L, T3D-RV, and variants that differ in LOT and monitored for induction of inflammatory anti-gluten T cells, anti-gluten and autoantibodies, and villous atrophy. These studies will reveal viral functional properties required for LOT, identify mechanistic links betwee viral tropism, host responses to infection, and tolerance abrogation, and provide an exemplary training platform for a career in science.
Celiac disease, an immune-mediated intestinal disorder triggered by exposure to dietary gluten, is a significant cause of morbidity in the United States and worldwide. The proposed research will uncover mechanisms underlying virus induction of complex immune disorders such as celiac disease. In turn, this knowledge will improve understanding of disease etiology and foster development of new personalized therapeutics to prevent this illness.
| Brown, Judy J; Jabri, Bana; Dermody, Terence S (2018) A viral trigger for celiac disease. PLoS Pathog 14:e1007181 |
| Brown, Judy J; Short, Sarah P; Stencel-Baerenwald, Jennifer et al. (2018) Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection. J Virol 92: |
| Wu, Allen G; Pruijssers, Andrea J; Brown, Judy J et al. (2018) Age-dependent susceptibility to reovirus encephalitis in mice is influenced by maturation of the type-I interferon response. Pediatr Res 83:1057-1066 |
| Bouziat, Romain; Hinterleitner, Reinhard; Brown, Judy J et al. (2017) Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356:44-50 |
| Baldridge, Megan T; Lee, Sanghyun; Brown, Judy J et al. (2017) Expression of Ifnlr1 on Intestinal Epithelial Cells Is Critical to the Antiviral Effects of Interferon Lambda against Norovirus and Reovirus. J Virol 91: |
