Rotavirus Infection Enhances Lipopolysaccharide-Induced Intussusception in a Mouse Model

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Abstract
Unexpected reports of intussusception after vaccination with the live tetravalent rotavirus vaccine RotaShield resulted in voluntary withdrawal of the vaccine. Intussusception, a condition in which the intestine acutely invaginates upon itself, is the most common cause of intestinal obstruction in children. We report here the development of a mouse model to study rotavirus-induced intussusception. In this model, both homologous murine and heterologous simian rotavirus strains significantly enhanced the rate of lipopolysaccharide (LPS)-induced intussusception, and this enhancement was replication dependent, requiring rotavirus doses of greater than one 50% infectious dose. Rotavirus-induced intussusceptions did not have observable lymphoid lead points, despite the induction of intestinal lymphoid hyperplasia after rotavirus infection. Intussusceptions are also postulated to result from altered intestinal motility, but rotavirus infection had no effect on gastrointestinal transit. LPS-induced intussusception is associated with the induction of inflammatory mediators, and intussusception rates can be modified by inflammatory antagonists. We show that rotavirus infection significantly enhanced serum tumor necrosis factor alpha and gamma interferon cytokine levels after LPS treatment compared to uninfected mice. Together, these data suggest that rotavirus infection sensitized mice to the inflammatory effects of subsequent LPS treatment to enhance intussusception rates.