ABSTRACTHuman noroviruses are the primary cause of severe childhood diarrhea in the United States, and they are of particular clinical importance in pediatric populations in the developing world. A major contributing factor to the general increased severity of infectious diseases in these regions is malnutrition—nutritional status shapes host immune responses and the composition of the host intestinal microbiota, both of which can influence the outcome of pathogenic infections. In terms of enteric norovirus infections, mucosal immunity and intestinal microbes are likely to contribute to the infection outcome in substantial ways. We probed these interactions using a murine model of malnutrition and murine norovirus infection. Our results reveal that malnutrition is associated with more severe norovirus infections as defined by weight loss, impaired control of norovirus infections, reduced antiviral antibody responses, loss of protective immunity, and enhanced viral evolution. Moreover, the microbiota is dramatically altered by malnutrition. Interestingly, murine norovirus infection also causes changes in the host microbial composition within the intestine but only in healthy mice. In fact, the infection-associated microbiota resembles the malnutrition-associated microbiota. Collectively, these findings represent an extensive characterization of a new malnutrition model of norovirus infection that will ultimately facilitate elucidation of the nutritionally regulated host parameters that predispose to more severe infections and impaired memory immune responses. In a broad sense, this model may provide insight into the reduced efficacy of oral vaccines in malnourished hosts and the potential for malnourished individuals to act as reservoirs of emergent virus strains.IMPORTANCEMalnourished children in developing countries are susceptible to more severe infections than their healthy counterparts, in particular enteric infections that cause diarrhea. In order to probe the effects of malnutrition on an enteric infection in a well-controlled system devoid of other environmental and genetic variability, we studied norovirus infection in a mouse model. We have revealed that malnourished mice develop more severe norovirus infections and they fail to mount effective memory immunity to a secondary challenge. This is of particular importance because malnourished children generally mount less effective immune responses to oral vaccines, and we can now use our new model system to probe the immunological basis of this impairment. We have also determined that noroviruses evolve more readily in the face of malnutrition. Finally, both norovirus infection and malnutrition independently alter the composition of the intestinal microbiota in substantial and overlapping ways.