Noroviruses (NoVs) are the most common cause of foodborne illnesses and acute non-bacterial gastroenteritis worldwide. The lack of a cell culture and animal model has hindered progress in understanding host susceptibility and host-viral interactions. Recently, NoVs have been identified as an important enteric pathogen of travelers' diarrhea. The principal investigator has a unique opportunity to study host genetic determinants and immune responses to NoV gastroenteritis in a large (n = 600) prospective cohort of US travelers to Mexico, India, or Peru. Our longterm goals are to: 1) to define important genetic determinants of susceptibility and mechanisms of host immunity to NoV infection to further vaccine development against NoVs, and 2) to identify vulnerable populations who may most benefit from vaccination. In order to achieve these goals, we propose the following specific aims: 1) to evaluate whether secretor status is an important determinant of risk of NoV infection, clinical severity of infection, and level of fecal viral shedding; 2) to study the role of preexisting antibodies to NoVs in protection against NoV infection; 3) to evaluate the cellular immune response elicited in subjects with NoV diarrhea. The 1st specific aim will be accomplished by secretor phenotyping with saliva specimens and genotyping from serum samples. NoV detection will be performed with quantitative real-time PCR and serum antibody conversion. The 2nd aim will be achieved by evaluating for preexisting anti-NoV antibodies and assessing for potential neutralization capacity of detected antibodies, with in vitro inhibition of VLP binding to histo-blood group antigen carbohydrates assays. The 3rd aim will be accomplished by measuring cytokines from fecal specimens and from NoV virus-like particle stimulation of peripheral blood mononuclear cells. The correlation between the intestinal immune response and the systemic immune response to NoV infection will be studied. This project will also provide essential training and skills for the development of the PI into a successful independent clinical investigator of enteric diseases. RELEVANCE (See instructions): NoVs are important enteric pathogens of foodborne diseases and infects approximately 23 million people annually in the US. Susceptible populations include restaurant patrons, children, elderly, institutionalized patients, the military, and travelers. With a low infectious dose, ease of transmission, environmental stability, and resistance to cleansing agents, NoVs are considered as a Category B candidate agent of bioterrorism.