Noroviruses are the most important cause of food-borne gastroenteritis worldwide and cause ~85-96% of selected outbreaks of acute non-bacterial gastroenteritis in the US. Heralded as the "stomach flu", retirement community outbreaks are pervasive and can result in 1-2% mortality rates in the elderly. Based on capsid sequences norovirus are divided into 5 genogroups. Genogroup I (GI) and II (GII) account for almost all human infections. Each genogroup is further divided into genotypes. The GII.4 genotype is the causative agent of 70-80% of all norovirus outbreaks worldwide. The norovirus major capsid protein forms an icosohedral shell, contains major antigenic determinants and interacts with histoblood group antigen (HBGA) carbohydrates, putative receptors for entry. This study investigates the molecular mechanisms governing norovirus capsid evolution, structure and HBGA recognition as a function of immune driven antigenic drift and deceptive imprinting. We identify the mechanisms by which replacement strains evolve over time, recognize new HBGA carbohydrate binding targets, and escape from highly penetrent host susceptibility alleles and protective herd immunity. While defining the relationships between mutation, antigenic variation, immunogenicity, deceptive imprinting, structure and HGBA binding, our interdisciplinary team simultaneously develops a robust GII.4 challenge model in swine and characterizes human monoclonal antibodies (mAb) to GI and GII strains, providing key reagents for advancing the field.

Public Health Relevance

for Noro grant Noroviruses are the most important cause of food-borne gastroenteritis worldwide and cause ~85-96% of selected outbreaks of acute non-bacterial gastroenteritis in the US. Noroviruses are transmitted via ingestion of fecally contaminated food and water, exposure to contaminated surfaces, aerosolized vomitus and direct person-to-person contact. The tremendous public health significance of norovirus is evidenced by the estimated ~23,000,000 infections, 50,000 hospitalizations, and 310 fatal cases in the US. In developing nations, repeat infection likely contribute to malnutrition in infants and young children and may result in death. This proposal tests the hypothesis that Norovirus strains evolve over time to use varying cellular receptors and avoid host immune surveillance. If this model is correct, then long-term strain specific protective immunity and immune prophylaxis can be formulated to protect against contemporary strain infections providing a much needed vaccination strategy against this important human pathogen.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-Q (02))
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Cassels, Frederick J
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University of North Carolina Chapel Hill
Public Health & Prev Medicine
Schools of Public Health
Chapel Hill
United States
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Lindesmith, Lisa C; Donaldson, Eric F; Beltramello, Martina et al. (2014) Particle conformation regulates antibody access to a conserved GII.4 norovirus blockade epitope. J Virol 88:8826-42
Debbink, Kari; Lindesmith, Lisa C; Baric, Ralph S (2014) The state of norovirus vaccines. Clin Infect Dis 58:1746-52
Debbink, Kari; Lindesmith, Lisa C; Ferris, Martin T et al. (2014) Within-host evolution results in antigenically distinct GII.4 noroviruses. J Virol 88:7244-55
Vega, Everardo; Donaldson, Eric; Huynh, Jeremy et al. (2014) RNA populations in immunocompromised patients as reservoirs for novel norovirus variants. J Virol 88:14184-96
Kirby, A E; Shi, J; Montes, J et al. (2014) Disease course and viral shedding in experimental Norwalk virus and Snow Mountain virus infection. J Med Virol 86:2055-64
Debbink, Kari; Lindesmith, Lisa C; Donaldson, Eric F et al. (2014) Chimeric GII.4 norovirus virus-like-particle-based vaccines induce broadly blocking immune responses. J Virol 88:7256-66
Swanstrom, Jesica; Lindesmith, Lisa C; Donaldson, Eric F et al. (2014) Characterization of blockade antibody responses in GII.2.1976 Snow Mountain virus-infected subjects. J Virol 88:829-37
Debbink, Kari; Lindesmith, Lisa C; Donaldson, Eric F et al. (2013) Emergence of new pandemic GII.4 Sydney norovirus strain correlates with escape from herd immunity. J Infect Dis 208:1877-87
Lindesmith, Lisa C; Costantini, Veronica; Swanstrom, Jesica et al. (2013) Emergence of a norovirus GII.4 strain correlates with changes in evolving blockade epitopes. J Virol 87:2803-13
Scheuer, Kelly A; Oka, Tomoichiro; Hoet, Armando E et al. (2013) Prevalence of porcine noroviruses, molecular characterization of emerging porcine sapoviruses from finisher swine in the United States, and unified classification scheme for sapoviruses. J Clin Microbiol 51:2344-53

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