The gnotobiotic piglet as a model for studies of disease pathogenesis and immunity to human rotaviruses
Gnotobiotic piglets serve as a useful animal model for studies of human rotavirus infections, including disease pathogenesis and immunity. An advantage of piglets over laboratory animal models is their prolonged 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 include: 1) the adaptation of the first human rotavirus to cell culture after passage and amplification in piglets; 2) delineation of the independent roles of the two rotavirus outer capsid proteins (VP4 and VP7) in induction of neutralizing antibodies and cross-protection; and 3) recognition of a potential role for a nonstructural protein (NSP4) in addition to VP4 and VP7, in rotavirus virulence. Current studies of the pathogenesis of group A human rotavirus infections in gnotobiotic piglets in our laboratory have confirmed that villous atrophy is induced in piglets given virulent but not cell culture attenuated human rotavirus (G1, P1 A, Wa strain) and have revealed that factors other than villous atrophy may contribute to the early diarrhea induced. A comprehensive examination of these factors, including a proposed role for NSP4 in viral-induced cytopathology, may reveal new mechanisms for induction of viral diarrhea. Finally, to facilitate and improve rotavirus vaccination strategies, our current emphasis is on the identification of correlates of protective active immunity in the piglet model of human rotavirus-induced diarrhea. Comparison of cell-mediated and antibody immune responses induced by infection with a virulent human rotavirus (to mimic 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 correlates 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). Secondly, there was a direct correlation between the degree of protection induced and the level of the intestinal immune response, with significantly higher local immune responses and complete protection induced only 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 usefulness of this model to examine new strategies for the design and improvement of human rotavirus vaccines.
KeywordsVillous Atrophy Gnotobiotic Piglet Ohio Agricultural Research Immune Colostrum Gnotobiotic Calf
Unable to display preview. Download preview PDF.
- 8.Kapikian AZ, Chanock RM (1990) Rotaviruses. BN Fields, Knipe DM, Chanock RM, Hirsch MS, Melnick JL, Monath TP, Roizman B, Straus SE (eds) Virology, Raven Press, New York, pp 1353–1403Google Scholar
- 12.Phillips RW, Tumbleson ME (1986) Models. In: Tumbleson ME (ed) Swine in Biomedical Research. Plenum Press, New York, pp 437–440Google Scholar
- 14.Saif LJ, Ward L, Yuan L, To TL (1996) Studies of the pathogenesis and immunity to a human rotavirus in a gnotobiotic pig model of enteric disease. Proc First Intl Rushmore Conf on Mechanisms in the Pathogenesis of Enteric Diseases, Rapid City, SD, September 27-30, 1995. Plenum Press, New YorkGoogle Scholar
- 19.Urasawa S, Hasegawa A, Urasawa T, Taniguchi K, Wakasugi F, Suzuki H, Inouye S, Pongprot B, Supawadee J, Suprasert S, Rangsiyanond, Tonusin S, Yamazi Y (1992) Antigenic and genetic analysis of human rotaviruses in Chiang Mai Thailand: evidence for a close relationship between human and animal rotaviruses. J Inf Dis 166: 227–234CrossRefGoogle Scholar
- 20.Van Cott J, Brim T, Lunney J, Saif LJ (1994) Contribution of antibody secreting cells induced in mucosal lymphoid tissues of pigs inoculated with respiratory or enteric strains of coronavirus to immunity against enteric coronavirus challenge. J Immunol 152: 3980–3990Google Scholar
- 22.Ward LA, Yuan L, Rosen BI, Saif LJ (1996) Local and systemic T cell immunity to human group A rotavirus in neonatal gnotobiotic pigs. Clin Diag Lab Immunol 3: 342–350Google Scholar