Semester

Summer

Date of Graduation

2010

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Christopher F. Cuff.

Abstract

Infectious diarrheal diseases are a major burden to human health worldwide. A proportion of those diarrheal diseases are caused by enteric viruses that gain access through the gastrointestinal tract. Consequently, the human gastrointestinal mucosa represents an important route of entry for enteric viruses. Enteric viruses are taken up by gastrointestinal mucosal dendritic cells (DCs) that induce and shape adaptive immunity, however, activation of mucosal DCs by enteric viruses is poorly understood. The research presented in this dissertation is focused on deciphering the requirements for activation of murine DCs in response to an enteric virus as well as the subsequent generation of adaptive immune responses. Respiratory enteric orphan virus (reovirus) was the model virus used to define the activation of type I interferon signaling events in infected bone marrow-derived DCs (BMDCs). The results suggest that reovirus escapes the DC endosome and viral dsRNA triggers non-TLR-3 pattern recognition receptors to induce IFN-beta production. IFN-beta positive feedback activates the type I IFN receptor and signals via NF-kappaB resulting in IFN-alpha induction. Additionally, mucosal and systemic virus-specific humoral responses were shown to be regulated by NF-kappaB. These results highlight signaling events for enteric virus-induced activation of DCs, potential modulation of specific adaptive responses by mucosal innate responses, and are the first to identify the requirement of NK-kappaB p50 for reovirus-induced IFN-beta induction by DCs. The activation of mucosal DCs presumably initiates the robust Th1-type immune response induced following oral reovirus infections in mice. Further studies were designed to determine if the induction of a robust anti-viral Th1-type immune response would inhibit the prototypic Th2-type peanut-specific food allergic response in an animal model of allergy and infection. IgE-mediated food allergies are an important cause of life-threatening hypersensitivity reactions. Allergy to peanuts is severe and sometimes fatal, and resolve in only about 20% of cases. The results demonstrate that reovirus did not alter peanut-specific serum IgE and IgG1 levels, but substantially increased the peanut-specific IgG2a response. These results demonstrate that an acute mucosal reovirus infection and subsequent Th1 immune response is capable of modulating the Th1/Th2 controlled humoral response to peanut suggesting that reovirus may have therapeutic implications as increased levels of non-allergenic peanut-specific IgG2a could block peanut antigens from binding to IgE-sensitized mast cells. Overall, this work provides new knowledge that may be exploited for the development of novel therapeutics for combating enteric viral infections as well as food allergies.

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