Pathogenesis of human norovirus in gnotobiotic pigs
Noroviruses (NoVs) cause gastroenteritis in humans, cattle and swine with high morbidity, but low mortality rates. Nevertheless, outbreak costs and loss of productivity are considerable. Human noroviruses (HuNoVs) are classified as class B biological pathogens that occur in communal settings and sporadically. Most NoVs (except murine NoV) are non-culturable, hampering their study. Expression of recombinant capsid proteins that self-assemble into virus-like particles (VLPs), and the construction of infectious replicons permitted limited in vitro studies. However, an animal model to study the pathogenicity of HuNoVs in vivo is lacking. Noroviruses belong to the Caliciviridae family. They contain single-stranded RNA genomes of positive polarity in which mutations and recombination have been described. Multiple NoV strains are present in the environment and mixed infections are common. The HuNoVs bind to histo-blood group antigens that are present on most human tissues; these antigens are also present in domestic animals and closely related NoV strains have been isolated from cattle and swine. Thus, these strains could have zoonotic potential or permit the appearance of human/animal recombinant strains. The first objective was to adapt a HuNoV strain to replicate in gnotobiotic (Gn) pigs. An animal disease model is critical to study the pathogenicity of HuNoVs and for future evaluation of immune responses and vaccine efficacy. We identified a HuNoV genogroup (G) II cluster 4 strain that replicated in Gn pigs causing mild diarrhea and brief fecal shedding, but as described in humans, some pigs were resistant to infection. Thus, the second objective was to determine if the pigs’ histo-blood group antigens (HBGA) play a role in HuNoV pathogenicity in swine as they do in humans. In an in vitro study, certain GI and GII HuNoV VLPs bound to pig tissues of the A or H phenotype. In an in vivo study, the expression of A/H antigens in intestinal tissues of Gn pigs was associated with GII HuNoV infection. To our knowledge this is the first study to compare the HBGA expression in the pig to the NoV infection outcome and to show that the Gn pig is a good model to study the pathogenesis of HuNoVs.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:gnotobiotic pig model norovirus pathogenesis histo blood group antigens calicivirus
Date of Publication:01/01/2006