Date of Graduation
School of Medicine
Microbiology, Immunology, and Cell Biology
Christopher F. Cuff.
Most pathogens invade the human body through mucosal surfaces. Enteric viruses are one such group of pathogens that are of great public health significance because they cause a number of serious diseases including gastroenteritis, hepatitis and poliomyelitis. Gastrointestinal disease is the second most common cause of morbidity worldwide, with diarrhea ranking first among infectious diseases in the categories of frequency and mortality in children. The mucosal epithelium provides the first line of defense against invading pathogens by serving as the first sensors of microbial infection and launching an innate immune response that leads to the development of adaptive immunity. An immunologic function of the mucosal epithelium is to mediate transcytosis of secretory immunoglobulin A (sIgA) from the lamina propria into the intestinal lumen. Transcytosis of IgA is dependent on the polymeric immunoglobulin receptor (pIgR) expressed by mucosal and glandular epithelial cells because one molecule of pIgR must be synthesized for each molecule of transported IgA. Thus, pIgR plays a role in mucosal host defense, and factors that influence expression of pIgR could affect mucosal immunity. This dissertation describes efforts to understand the role of intestinal epithelial cells (IECs) as an active participant of mucosal immunity during enteric virus infection. We used reovirus to demonstrate that a newly appreciated role of the IECs in responding to infection is upregulation of pIgR expression, which appears to serve as an innate host defense mechanism. Our studies demonstrate that reovirus upregulates pIgR expression in the intestinal epithelial cell line HT-29 in a replication independent fashion, and that binding of virus to cellular receptors and partial disassembly of virus inside acidified endosomes are required steps for this innate immune response by IECs. In addition, we demonstrate that activation of calpain and NFkappaB signaling and reovirus-induced PIGR gene transcription in IECs upregulate pIgR expression during infection. Signaling induced by virus-host interaction might serve to augment pIgR-mediated transcytosis of IgA in vivo, thereby linking the innate and acquired immune responses to enteric viruses. Our studies will contribute to improving human health by advancing understanding of IEC biology and function, viral pathogenesis, and induction of innate and adaptive immunity to viruses, particularly in the intestine.
Pal, Kasturi, "Regulation of polymeric immunoglobulin receptor by reovirus in intestinal epithelial cells" (2006). Graduate Theses, Dissertations, and Problem Reports. 2400.