Norovirus infection pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Noroviruses are highly contagious, given that as few as 10 particles are enough to cause the disease, transmission is via the fecal-oral route and peaks during the period when symptoms are most severe, and up to 3 days after recovery. As many strains of noroviruses exist, immunity is not gained following an infection. A non-functional fucosyltransferase FUT2 mutation has been associated with protection against the most common norovirus strains as FUT2 is required for viral transport in the small intestine.
Pathophysiology
Structure
- Noroviruses contain a positive-sense RNA genome of approximately 7.5 kbp, encoding a major structural protein (VP1) of about 58~60 kDa and a minor capsid protein (VP2).[1]
- The virus particles demonstrate an amorphous surface structure when visualized using electron microscopy and are between 27-38 nm in size.[2]
- The most variable region of the viral capsid is the P2 domain, which contains antigen-presenting sites and carbohydrate-receptor binding regions.[3][4][5]
- The estimated mutation rate (1.21 x 10−2 to 1.41 x 10−2 substitutions per site per year) in this virus is high even compared with other RNA viruses.[6]
Transmission
- Although presymptomatic viral shedding may occur, shedding usually begins with onset of symptoms and may continue for 2 weeks after recovery.
- The highest risk of transmission is during the peak of symptoms, and during the first 3 days of the recovery phase.
- It is unclear to what extent viral shedding over 72 hours after recovery signifies continued infectivity.[7]
- The fecal-oral route is the most common route of transmission of the virus from person to person or via contaminated food, water, or fomites.
- The norovirus can survive for long periods outside a human host depending on the surface and temperature conditions: 12 hours on hard surfaces, and up to 12 days on contaminated fabrics,[8] and it can survive for months, maybe even years in contaminated still water.[9] A study done in 2006 found the virus on several surfaces used for food preparation 7 days after contamination.[10]
- Noroviruses are highly contagious and as few as 10 viral particles may be sufficient to infect an individual.
- Shellfish and salad ingredients are the foods most often implicated in norovirus outbreaks. Ingestion of shellfish that have not been sufficiently heated poses a high risk for norovirus infection. Foods other than shellfish may be contaminated by infected food handlers.[11]
Genetics
- A non-functional fucosyltransferase FUT2 provides high protection from the most common norovirus GII.4.[12]
- Functional FUT2 fucosyltransferase transferes a fucose sugar to the end of the Histo-blood group ABO(H) precursor in gastrointestinal cells as well as saliva glands. The ABH antigen produced is thought to act as receptors for human norovirus. Homozygous carriers of any nonsense mutation in the FUT2 gene are called non-secretors as no ABH antigen is produced.
- Approximately 20% of Caucasians are non-secretors due to the G428A and C571T nonsense mutations in FUT2 and therefore have strong although not absolute protection from the norovirus GII.4.[13]
- Non-secretors can still produce ABH antigens in erythrocytes as the precursor is formed by FUT1.[14] Some norovirus genotypes (GI.3) can infect non-secretors.[15]
- Of individuals who are secretor positive, those with blood type O were more likely to be infected and B less likely.[16][17][18]
- Reports have shown a link between the expression of human histo-blood group antigens (HBGAs) and the susceptibility to norovirus infection. Studies have suggested the viral capsid of noroviruses may have evolved from selective pressure of human HBGAs.[19]
- A 2008 study suggests the protein MDA-5 may be the primary immune sensor that detects the presence of noroviruses in the body.[20] Interestingly, some people have common variations of the MDA-5 gene that could make them more susceptible to norovirus infection.[21]
- A 2010 study suggested a specific genetic version of norovirus (which would not be distinguishable from other types of the virus using standard viral antibody tests) interacts with a specific mutation in the ATG16L1 gene to help trigger symptomatic Crohn's disease in mice that have been subjected to a chemical that causes intestinal injury similar to the process in humans (there are other similar ways for such diseases to happen like this, and this study in itself does not prove norovirus causes Crohn's in humans).
References
- ↑ Clarke IN, Lambden PR (2000). "Organization and expression of calicivirus genes". J. Infect. Dis. 181 Suppl 2: S309–16. doi:10.1086/315575. PMID 10804143.
- ↑ Prasad BV, Crawford S, Lawton JA, Pesavento J, Hardy M, Estes MK (2001). "Structural studies on gastroenteritis viruses". Novartis Found. Symp. Novartis Foundation Symposia. 238: 26–37, discussion 37–46. doi:10.1002/0470846534.ch3. ISBN 978-0-470-84653-7. PMID 11444031.
- ↑ Jiang X, Tan M, Hegde RS (2004). "The P Domain of Norovirus Capsid Protein Forms Dimer and Binds to Histo-Blood Group Antigen Receptors". J. Virol. 78 (12): 6233–42. doi:10.1128/JVI.78.12.6233-6242.2004. PMC 416535. PMID 15163716.
- ↑ Tan M, Huang PW, Meller J, Zhong WM, Farkas T, Jiang X (2004). "Mutations within the P2 domain of norovirus capsid affect binding to human histo-blood group antigens: evidence for a binding pocket". J. Virol. 78 (6): 3201. doi:10.1128/JVI.78.6.3201.2004.
- ↑ Cao S, Lou ZY, Tan M, Chen YT, Liu YJ, Zhang ZS, Zhang XJC (2007). "Structural Basis for the Recognition of Blood Group Trisaccharides by Norovirus". J. Virol. 81 (11): 5949–57. doi:10.1128/JVI.00219-07. PMC 1900264. PMID 17392366.
- ↑ Victoria M, Miagostovich MP, Ferreira MS, Vieira CB, Fioretti JM, Leite JP, Colina R, Cristina J (2009). "Bayesian coalescent inference reveals high evolutionary rates and expansion of Norovirus populations". Infect Genet Evol. 9 (5): 927–932.
- ↑ Morillo SG, Timenetsky Mdo C (2011). "Norovirus: an overview". Revista Da Associação Médica Brasileira (1992). 57 (4): 453–8. PMID 21876931. Unknown parameter
|month=ignored (help) - ↑ http://www.phac-aspc.gc.ca/id-mi/norovirus-eng.php
- ↑ http://blogs.scientificamerican.com/artful-amoeba/2012/01/17/misery-inducing-norovirus-can-survive-for-months-perhaps-years-in-drinking-water/
- ↑ http://www.ncbi.nlm.nih.gov/pubmed/16473426
- ↑ Parashar UD, Monroe SS (2001). ""Norwalk-like viruses" as a cause of foodborne disease outbreaks". Rev. Med. Virol. 11 (4): 243–52. doi:10.1002/rmv.321. PMID 11479930.
- ↑ Carlsson B, Kindberg E, Buesa J, Rydell GE, Lidón MF, Montava R, Abu Mallouh R, Grahn A, Rodríguez-Díaz J, Bellido J, Arnedo A, Larson G, Svensson L. (2009). "The G428A Nonsense Mutation in FUT2 Provides Strong but Not Absolute Protection against Symptomatic GII.4 Norovirus Infection". PLOS one. doi:10.1371/journal.pone.0005593. PMID 19440360. Unknown parameter
|month=ignored (help) - ↑ Rydell GE, Kindberg E, Larson G, Svensson L (2011). "Susceptibility to winter vomiting disease: a sweet matter". Rev. Med. Virol. 21 (6): 370–82. doi:10.1002/rmv.704. PMID 22025362. Unknown parameter
|month=ignored (help) - ↑ Shirato H (2011). "Norovirus and histo-blood group antigens". Jpn. J. Infect. Dis. 64 (2): 95–103. PMID 21519121.
- ↑ Nordgren J, Kindberg E, Lindgren PE, Matussek A, Svensson L (2010). "Norovirus gastroenteritis outbreak with a secretor-independent susceptibility pattern, Sweden". Emerg. Infect. Dis. 16 (1): 81–7. doi:10.3201/eid1601.090633. PMID 20031047. Unknown parameter
|month=ignored (help) - ↑ "Norovirus and histo-blood group antigens". Retrieved 22 December 2012.
- ↑ Hutson, AM (July 2003). "Norwalk virus infection and disease is associated with ABO histo-blood group type". J. Infect. Dis. 188 (1): 176–7. doi:10.1086/375829. PMID 12825190. Unknown parameter
|coauthors=ignored (help) - ↑ Le Guyader FS, Krol J, Ambert-Balay K, Ruvoen-Clouet N, Desaubliaux B, Parnaudeau S, Le Saux JC, Ponge A, Pothier P, Atmar RL, Le Pendu J (2010). "Comprehensive Analysis of a Norovirus-Associated Gastroenteritis Outbreak, from the Environment to the Consumer". Journal of Clinical Microbiology. 48 (3): 915–20. doi:10.1128/JCM.01664-09. PMC 2832421. PMID 20053852. Unknown parameter
|month=ignored (help) - ↑ Shirato H (2011). "Norovirus and histo-blood group antigens". Japanese Journal of Infectious Diseases. 64 (2): 95–103. PMID 21519121.
- ↑ McCartney SA, Thackray LB, Gitlin L, Gilfillan S, Virgin Iv HW, Colonna M (July 18, 2008). Baric, Ralph S., ed. "MDA-5 Recognition of a Murine Norovirus". PLoS Pathog. 4 (7): e1000108. doi:10.1371/journal.ppat.1000108. PMC 2443291. PMID 18636103. Unknown parameter
|unused_data=ignored (help) - ↑ Researchers Discover Primary Sensor That Detects Stomach Viruses Newswise, Retrieved on July 20, 2008.