Mucosal Dendritic Cell Function Following Enteric Virus Infection

The mucosal immune system must remain tolerant to commensal bacteria and food antigens, yet still maintain the capacity to trigger inflammatory responses to pathogenic microorganisms. The process of initiating inflammatory adaptive immune responses to infection is controlled by multiple populations of dendritic cells (DCs) in the intestinal mucosa. Although it is widely accepted that microbial pathogen associated molecular patterns trigger pattern recognition receptors (PRRs) in DCs, a clear picture as to what factors force dendritic cells into initiating inflammatory responses has not yet emerged. <P> Understanding the processes of how DCs initiate inflammatory responses to enteric virus infection will enhance success in developing mucosal vaccines, which directly addresses the purpose of the RFA entitled Immune Defense Mechanisms at the Mucosa. Enteric reovirus infection induces robust Th1- type immune responses in the intestine that is characterized by production of IFN-?, activation of virus-specific CD8+ cytotoxic T-cells, and appearance of abundant antigen-specific serum antibody of the IgG2a subclass. <P> These observations, along with additional preliminary data support the central hypothesis of this project that the Th1-promoting adjuvant effect of reovirus is due to activation of dendritic cells by cell-free or cell-associated virions, and requires transient viral gene transcription for full activity. Viral gene transcription leads to DC activation through signaling mediated by the intracellular PRRs RIG-1/MDA-5, which induces mucosal DCs to produce Th1 polarizing cytokines such as IL-12. <P> The overall goal of this project is to produce a clearer understanding of how mucosal DCs are stimulated by enteric viruses, thus providing opportunities for advancing the field of mucosal vaccine development. <P> The central hypothesis will be tested with the following Specific Aims: 1) Compare the capacities of replication competent and replication incompetent virus to activate mucosal DCs and macrophages as a result of signaling through intracellular antiviral PRRs, 2) Evaluate the responses of mucosal DCs to cell free reovirus and reovirus-infected IECs, and 3) Demonstrate the capacity of virus-infected mucosal DCs to polarize naive cells to a Th1 phenotype, and determine the role of IL-12 in this response. <P> RELEVANCE: There are up to 2.5 million deaths per year worldwide from food and water-borne diarrheal disease, and it has been estimated that nearly 80% of food-borne illnesses in the United States are due to enteric viruses. Besides gastroenteritis, other diseases caused by enteric viruses include hepatitis, myocarditis, and inflammation of the central nervous system. This project will improve knowledge of how the intestinal immune system initially responds to enteric viruses, and this information will aid in development of vaccines against viruses that invade through the gastrointestinal tract.