Norovirus

HUMAN NOROVIRUSES

HuNoVs were first identified in 1972 (Norwalk agent) from fecal isolates from a 1968 gastroenteritis outbreak in Norwalk, Ohio. HuNoVs are nonenveloped, positive-sense, single-strand RNA viruses belonging to the Norovirus genus in the Caliciviridae family of viruses. HuNoVs are divided into 10 genogroups (GI to GX) and further subdivided into genotypes. GI, GII, GIV, and GVIII NoVs infect humans ( Fig. 43.1A ); of these, GI and GII are the most important for human infection. GII and GIV viruses also infect porcine and canines, respectively, indicating hypothetical zoonotic transmission routes that have not been rigorously evaluated, ^, although antibodies against canine NoVs have been detected in humans.

HuNoVs have a 7.5–8.0-kb genome surrounded by an icosahedral capsid. The genome has a 5-prime VPg cap and a 3-prime poly(A) tail and contains three open reading frames (ORFs). ORF1 encodes a nonstructural polyprotein. ORF2 encodes the major capsid structural protein, VP1, which forms 90 dimers that self-assemble into the icosahedral capsid. ORF3 encodes a minor structural protein, VP2, which increases capsid stability and VP1 expression. VP1 is composed of two domains, shell (S) and protruding (P), separated by a short hinge sequence. The P domain is further subdivided into the highly conserved P1 and hypervariable P2 subdomains. ^, Variation in the P2 subdomain regulates strain-specific ligand binding and antigenicity.

New HuNoV strains emerge via several mechanisms, including recombination and progressive quasispecies variation. Recombination events, such as the emergence of the GII.P16 polymerase with GII.2, GII.3, GII.4, and GII.13 capsids, may increase pandemic potential for human noroviruses, however this has not been proven. Quasispecies are formed during viral replication with the error prone RNA-dependent RNA polymerase; the resulting antigenic drift primarily occurs within neutralizing/blockade antibody epitopes of the surface-exposed P2 domain. ^{, ,} There is mounting evidence that children serve as important reservoirs for prepandemic GII.4 strains, emphasizing the importance of vaccinating young children for the control of norovirus infection in the general population.

NOROVIRUS TRANSMISSION AND DISEASE

HuNoVs are classically transmitted by the fecal–oral route, but can also be transmitted via aerosolized vomitus, ^, contaminated food or water ^, and fomites. Transmission is facilitated by the ability of HuNoVs to remain stable for weeks on surfaces and >1 year in water samples. ^, In the United States and United Kingdom, norovirus is the leading cause of viral food-borne illness and death. ^, Chemical disinfection is the only potential intervention in the transmission cycle, but classic hygiene measures, including alcohol-based hand washing, and measures to prevent food contamination have proven largely ineffective.

As few as 18 viral particles are capable of causing infection and each gram of feces may contain up to 5 billion infectious doses. HuNoVs are highly contagious and easily transmitted in semiclosed communities, such as senior care homes, cruise ships, and military barracks, and are common nosocomial infections in the United States and Europe. ^, Additionally, up to 30% of HuNoV infections result in asymptomatic shedding; the role of asymptomatic infection in transmission and outbreaks of norovirus remains unclear. ^, However, studies have demonstrated that the viral load of HuNoV differs little between symptomatic and asymptomatic infections, suggesting that asymptomatic shedding may play a significant role in outbreak dynamics.

HuNoV gastroenteritis is commonly referred to as the “stomach flu” and has also earned the nickname “winter vomiting disease” based on its distinct winter seasonality pattern in the Northern Hemisphere, with most infections occurring between November and April. HuNoVs have an incubation period of approximately 24 hours and most people with illness are typically symptomatic for 24–72 hours. HuNoV-induced gastroenteritis commonly presents as nausea, (projectile) vomiting, and diarrhea, but can also include cramps, fever, headache, and dehydration. ^{, ,} HuNoV-induced gastroenteritis induces longer duration and more frequent vomiting compared with bacterial gastroenteritis. Approximately 10% of individuals with norovirus gastroenteritis seek medical attention, which might include hospitalization and treatment for dehydration with oral or intravenous fluid therapy. Norovirus infection can also become an important factor contributing to a poor outcome in patients with underlying cardiac and renal conditions.

HuNoV disease burden is borne by the most vulnerable populations. Children under the age of 5 are most likely to need medical care for norovirus infection suffering primarily from diarrhea, vomiting, and fever. After young children, persons ≥65 years are most at risk of severe disease. In upper–middle and high-income countries, the aged suffer higher hospitalization rates, longer hospital stays and more severe disease compared to children <5 years. ^{, ,} In the United States, >75% of norovirus outbreaks may occur in long-term care facilities. The burden of norovirus is anticipated to rise as an increasing proportion of society becomes elderly, with an increased need for institutionalized care. Although a self-limiting infection in an immunocompetent patient, chronic HuNoV infection can develop in immunocompromised hosts, which is associated with longer durations of diarrhea and shedding. In rare cases, necrotizing enterocolitis in preterm infants and inflammatory bowel disease also have been reported in association with norovirus infection, although a causal link has not been established.

HISTO-BLOOD GROUP ANTIGENS AND OTHER ESSENTIAL COFACTORS

Histo-blood group antigens (HBGAs) are receptors or essential cofactors for HuNoV infection. HBGAs are a large family of complex carbohydrates classified by terminal glycosylation moieties: secretor (H), Lewis (Le), and A or B antigen. In individuals who are secretor-positive, HBGAs are expressed on the surface of epithelial cells lining mucosal surfaces and are found free in mucosal secretions. In secretor-negative individuals, only core HBGA chains with minimal branch glycosylation are expressed and secreted. Specific branch glycosylation is associated with susceptibility to HuNoV infection and HuNoVs bind HBGAs in strain-specific and genotype-­specific patterns in vitro. It is hypothesized that HBGA expression levels and profiles, HuNoV HBGA-binding profiles, and virus titers may regulate infection patterns in human populations. In support, individuals expressing B antigen are more resistant to GI.1 HuNoV infection, whereas secretor-positive individuals are more likely to be infected with certain HuNoV genotypes, including GII.4, the dominant genotype causing human disease worldwide. However, a birth cohort study in Ecuadorian children showed that secretor-negative infants experienced a similar burden of illness as secretor-positive children. Thus, even though a secretor-negative phenotype is associated with a reduced risk of infection, it is not completely protective against all HuNoV strains. ^{, ,} Recent evidence of bile-enhanced GII.1 and GII.2 virus-like particle (VLP) in vitro binding to natural carbohydrate ligands and enhanced in vitro growth of GII.3, GII.17, and GI.1 HuNoV supports the requirement of some HuNoV strains for attachment cofactors in addition to HBGAs. In addition to bile, metal ions may also be essential cofactors for some HuNoV via strain-specific, undefined mechanisms.