THE GNOTOBIOTIC PIGLET AS A MODEL FOR STUDIES OF DISEASE PATHOGENESISAND IMMUNITY TO HUMAN ROTAVIRUSES

Gnotobiotic piglets serve as a useful animal model for studies of huma n rotavirus infections, including disease pathogenesis and immunity. A n advantage of piglets over laboratory animal models is their prolonge d susceptibility to human rotavirus-induced disease, permitting cross- protection studies and an analysis of active immunity. Major advances in rotavirus research resulting from gnotobiotic piglet studies includ e: 1) the adaptation of the first human rotavirus to cell culture afte r passage and amplification in piglets; 2) delineation of the independ ent roles of the two rotavirus outer capsid proteins (VP4 and VP7) in induction of neutralizing antibodies and cross-protection; and 3) reco gnition of a potential role for a nonstructural protein (NSP4) in addi tion to VP4 and VP7, in rotavirus virulence. Current studies of the pa thogenesis of group A human rotavirus infections in gnotobiotic piglet s in our laboratory have confirmed that villous atrophy is induced in piglets given virulent but not cell culture attenuated human rotavirus (G1, P1A, Wa strain) and have revealed that factors other than villou s atrophy may contribute to the early diarrhea induced. A comprehensiv e examination of these factors, including a proposed role for NSP4 in viral-induced cytopathology, may reveal new mechanisms for induction o f viral diarrhea. Finally, to facilitate and improve rotavirus vaccina tion strategies, our current emphasis is on the identification of corr elates of protective active immunity in the piglet model of human rota virus-induced diarrhea. Comparison of cell-mediated and antibody immun e responses induced by infection with a virulent human rotavirus (to m imic host response to natural infection) with those induced by a live attenuated human rotavirus (to mimic attenuated oral vaccines) in the context of homotypic protection has permitted an analysis of correlate s of protective immunity. Results of these studies have indicated that the magnitude of the immune response is greatest in lymphoid tissues adjacent to the local site of viral replication (small intestine). Sec ondly, there was a direct correlation between the degree of protection induced and the level of the intestinal immune response, with signifi cantly higher local immune responses and complete protection induced o nly after primary exposure to virulent human rotavirus. These studies thus have established basic parameters related to immune protection in the piglet model of human rotavirus-induced disease, verifying the us efulness of this model to examine new strategies for the design and im provement of human rotavirus vaccines.