Reovirus will be used as a probe of the possible roles of murine gut associated lymphoid tissues (GALT) in resistance to and resolution of viral infections commencing via the intestinal route. We will focus on local priming in Peyer's patches (PP) of specific T-helper (TH) and T-cytotoxic (TC) lymphocyte populations and on any special propensity these may display for selective circulation through and/or lodging in the rest of the intestines in lamina propria (LPL) or intraperitoneal (IEL) effector T cell compartments. Thus the efficacies of various virus-specific TH- and TC-populations from different tissues primed by different routes at limiting and containing reovirus (type 3 hemagglutinin) in the gut and protecting vs. ordinarily lethal brain infection will be tested. Further, the possible potentiation by enterically delivered reovirus of non-specific naturally occurring cytotoxicity in PP, LPL, and IEL cell populations will be assayed since perturbations in natural killer and/or naturally cytotoxic cell populations may also have significance in both viral infections and oncogenic processes in the gut. A library of serotypes of reovirus and their genetic reassortants that differ in tissue tropisms, resistance to intestinal digestive enzymes, and sites of replication will be utilized to try to correlate particular viral polypeptides with efficacy of specific T cell priming in PP and the generation of protective immunity. Particular variants of reovirus, for instance one with the neurotropism of type 3 and the resistance to intestinal digestion of type 1, will be chosen to produce model infections for assay of functional activity of specific T cells in vivo. Identification of particular viral polypeptides with effective priming of PP lymphocytes may eventually lead to the construction of more general and effective gut mucosal vaccines. Two of our recent main findings that lend encouragement to our proposed program are: 1) the novel finding of sharply elevated numbers of precursors for viral-specific TC-lymphocytes in PP following an enteric virus infection; and 2) the dramatic rise in PP viral-specific precursors for antibody-secreting clones and in a high incidence of these becoming committed to secretory antibody (IgA) production. Both these perturbations followed intraduodenal infection with type 1 reovirus, a serotype with a special propensity to adhere to dome epithelium of PP, and support the potency of reovirus as a gut mucosal antigenic stimulus of both T- and B-cell compartments.
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