A Mouse Model for Human Norovirus

S.T. and A.O.K. contributed equally to this work. ABSTRACT Human noroviruses (HuNoVs) cause significant morbidity andmortality worldwide. However, despite substantial efforts, a small-animal model for HuNoV has not been described to date. Since “humanized ” mice have been successfully used to study human-tropic pathogens in the past, we challenged BALB/c mice deficient in recombination activation gene (Rag) 1 or 2 and common gamma chain (c) (Rag-c) engrafted with human CD34 hematopoietic stem cells, nonengrafted siblings, and immunocompetent wild-type controls with pooled stool isolates from patients positive for HuNoV. Surprisingly, both human-ized and nonhumanized BALB/c Rag-c-deficient mice supported replication of a GII.4 strain of HuNoV, as indicated by in-creased viral loads over input. In contrast, immunocompetent wild-type BALB/c mice were not infected. An intraperitoneal route of infection and the BALB/c genetic background were important for facilitating a subclinical HuNoV infection of Rag-c-deficient mice. Expression of structural and nonstructural proteins was detected in cells with macrophage-like morphology in the spleens and livers of BALB/c Rag-c-deficient mice, confirming the ability of HuNoV to replicate in a mouse model. In sum-mary, HuNoV replication in BALB/c Rag-c-deficient mice is dependent on the immune-deficient status of the host but not on the presence of human immune cells and provides the first genetically manipulable small-animal model for studying HuNoV in-fection. IMPORTANCE Human noroviruses are a significant cause of viral gastroenteritis worldwide, resulting in significant morbidity an