The gnotobiotic piglet as a model for studies of disease pathogenesis and immunity to human rotaviruses

Abstract

Summary. Gnotobiotic piglets serve as a useful animal model for studies of human rotavirus infections, including disease pathogenesis and immunity. An advantage of piglets ov~r 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 rota virus 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 (Gl, PIA, Wa strain) and have revealed that factors other than villous atrophy may contribute to the early diarrhea induced. A comprehensive ~xamination 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 rota virus (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 154 L. J. Saif et al. 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 rota virus vaccines.

Cytokine Responses in Gnotobiotic Pigs after Infection with Virulent or Attenuated Human Rotavirus

“…The pair of virulent and attenuated Wa HRV strains provides a valuable tool to study the relationship between cytokine profiles, kinetics, and magnitude of responses and their relationships to the pathogenicity and immunity induced by these two rotavirus strains that differ in virulence (34,35). The pathogenicity of and immune responses to VirHRV and AttHRV have been well defined in gnotobiotic pigs (3,4,45,46,49,51).…”

Membrane markers of the immune cells in swine: an update

“…These studies concluded that piglets are immunocompetent at birth [22], albeit with a largely 'immature' immune system that has not been previously in contact with antigens, resulting in a primary immune response, a less developed mucosal immune response and lower repertoire diversity than in adults [182]. Piglets also constitute a unique material for studying the development of the postnatal immune response [120] without any other antigenic stimulus, since they can be reared in germ-free [179,222] and antigen-free environments [108,129]. However, certain characteristics of the porcine lymphoid system may affect the immune system, and thus require the development of appropriate cellular and molecular reagents and tools [184].…”

Animal models of enteroaggregativeEscherichia coliinfection

“…Pigs are monogastrics and leverage the gastrointestinal, nutritional, metabolic and immunologic similarities of humans. [91][92][93] neonatal and weaned C57bl/6 mouse model with or without malnutrition. Another neonatal model was developed more recently using six-day-old C57BL/6 mice to study EAEC induced infantile diarrhea.…”