Rotavirus infection and the ensuing gastroenteritis remain a leading cause of morbidity and mortality worldwide.
The aims of this proposal are to continue and to extend studies of the immune mechanisms responsible for the resolution of primary rotavirus infection and protection from reinfection in a murine model and in humans.
The specific aims are: ? 1) To define the effector mechanisms responsible for protection from rotavirus infection in mice immunized with live virus via the enteric, respiratory and parenteral routes. Immunization via each of these routes can induce short-term protective immunity in mice, but we hypothesize that the effector mechanisms responsible for this immunity, the level of immunity, and its duration may differ depending on the immunization route. We also predict that different routes of antigen delivery will initiate distinct lymphocyte trafficking programs for both T and B cells and that these distinct programs will lead to differences in protection. ? 2) To study people directly in order to better characterize the immune response to rotavirus, with specific emphasis on lymphocytes and lymphocyte trafficking signals in the gut. We hypothesize that rotavirus specific B cells resident in the GI tract will be quantitatively and qualitatively different from such cells in the circulation and that the number and phenotype of these cells will be a better indicator of functional immune status than circulating antibody levels. ? 3) To identify components of the interferon and acquired immune systems responsible for restricting systemic (non-GI tract) replication of rotavirus and to use viral genetics to identify rotavirus genes associated with enhanced systemic replication in the absence of interferon. It is our hypothesis that interferons are critically important in restricting the systemic replication of rotavirus early in infection, especially in organs such as the liver and pancreas, and that specific rotavirus genes can be linked to the restrictive interferon effect. We also predict that specific components of the acquired immune system are involved in modulating systemic rotavirus replication and these may differ from those involved in restricting mucosal replication. ? ? ?
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