A viral enterotoxin - A new mechanism of virus-induced pathogenesis

Acute infectious gastroenteritis is a major cause of infant morbidity in de veloped countries and of infant mortality in developing areas of the world. Rotavirus is recognized as the most important etiologic agent of infantile gastroenteritis, and studies of rotavirus serve as models to understand th e complex interactions between enteric viruses and the multifunctional cell s of the gastrointestinal tract. Understanding such interactions is signifi cant for microbial pathogenesis because most (>80%) infections are initiate d at mucosal surfaces. Rotaviruses are pathogens that infect the mature ent erocytes of the villi in the intestine and infection appears to be Limited to these highly differentiated cells in immunologically competent hosts. In such hosts, infections are generally acute yet diarrheal disease can be se vere and life-threatening. Disease generally is resolved within 2-5 days af ter infection if affected hosts receive adequate rehydration, In immunocomp romised hosts, virus infections persist, virus can be detected extraintesti nally and virus excretion may be detected for extended periods of time (man y months). Rotaviruses infect almost all mammalian and some avian species and much of our understanding of rotavirus pathogenesis has come from studies in animal models, particularly in small animal models (mice and rabbits), but also i n larger animals (cows and piglets). Studies in children are limited due to the difficulty and lack of clinical need of obtaining biopsies from infant s and the inability to determine the precise time of natural infections. In all animal species where naive animals can be infected, disease is age-dep endent; for example, in mice and rabbits, diarrheal disease is the outcome of infections that occur only during the first two weeks of life (Ciarlet e t al., 1998; Starkey et al., 1986; Ramig 1988; Ward et al.. 1990: Burns et ai., 1995), while animals remain susceptible to viral infection into adulth ood. Rotavirus infections have been reported to occur repeatedly in humans from birth to old age, but the majority of infections after the first 2 yea rs of life are asymptomatic or associated with mild gastrointestinal sympto ms. The age-related resistance to rotavirus-induced diarrhea in humans is t hought to be mediated primarily by acquired immunity, but it is not possibl e to directly test if humans also exhibit an age-dependent resistance to di sease based on other factors such as intestinal development and maturation. Currently our best understanding of the mechanisms of rotavirus pathogenes is rely on results obtained in animal models.