Pathogenesis of Intestinal and Systemic Rotavirus Infection

Abstract

Rotaviruses are responsible for significant gastrointestinal disease, primarily in children Ͻ5 years of age and the young of other mammalian species.Each year rotaviruses cause approximately 111 million episodes of gastroenteritis in children, which result in 25 million visits to clinics, 2 million hospitalizations, and 352,000 to 592,000 deaths.On a worldwide basis, nearly every child experiences rotavirus gastroenteritis by age 5, 1 in 5 visits a clinic, 1 in 65 is hospitalized, and 1 in 293 dies.Children in the poorest countries account for 82% of rotavirus deaths (60).This disease burden underscores a need for interventions such as vaccines.A vaccine was developed and approved, but recommendation for its use was withdrawn because of vaccination-associated adverse events (57).Additional information about the molecular biology, immunology, and pathogenesis of rotavirus infection will inform ongoing vaccine development efforts.Our understanding of rotavirus-induced diarrheal disease is incomplete compared to that of several other pathogens (e.g., cholera).Rotavirus diarrhea has been attributed to several different mechanisms, including malabsorption secondary to enterocyte destruction, a virus-encoded toxin, stimulation of the enteric nervous system (ENS), and villus ischemia (13, 45).Over the past several years, numerous studies have addressed mechanisms of diarrhea induction at the cellular and tissue levels, and a new understanding of the mechanisms is beginning to emerge.Here I will briefly outline the new data and present our current understanding of how rotaviruses induce diarrhea in the infected host.Recent studies confirm sporadic case reports that rotavirus infection is not confined to the intestine as was generally assumed.Although systemic sequellae to rotavirus infection are apparently rare, reports have continually appeared in the literature, and recent work with animal models has begun to shed light on how the virus spreads to extraintestinal sites.Our current understanding of extraintestinal spread and infection will also be considered below. GENERAL CHARACTERISTICS OF ROTAVIRUS INFECTION AND DISEASE IN HUMANS AND ANIMALSRotavirus.Rotaviruses comprise a genus within the family Reoviridae.The rotavirion has a nonenveloped, complex, triple-layered capsid structure that surrounds a genome com-