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== Virology ==
== Virology ==
=== Transmission ===
=== Transmission ===
Noroviruses are transmitted directly from person to person (62–84% of all reported outbreaks)<ref>{{cite journal | author = Moore MD, Goulter RM, Jaykus L | title = Human Norovirus as a Foodborne Pathogen: Challenges and Developments | journal = Annual Review of Food Science and Technology (2015) | volume = 6 | issue = 1 | pages = 411–33 | date = April 2015 | doi = 10.1146/annurev-food-022814-015643 | url = http://www.annualreviews.org/doi/full/10.1146/annurev-food-022814-015643 }}</ref> and indirectly via contaminated water and food. They are extremely contagious, and fewer than twenty virus particles can cause an infection<ref name="pmid21876931"/> (some research suggests as few as five).<ref name=juan/> Transmission can be [[aerosolized]] when those stricken with the illness vomit, and can be aerosolized by a toilet flush when vomit or diarrhea is present; infection can follow eating food or breathing air near an episode of vomiting, even if cleaned up.<ref>[http://www.newscientist.com/article/mg16722551.000-ive-lost-my-appetite.html "I've lost my appetite...": New Scientist article on spread of viral food poisoning across a restaurant by eating near where someone has vomited]</ref> The viruses continue to be shed after symptoms have subsided and shedding can still be detected many weeks after infection.<ref>{{cite journal | author = Atmar RL, Opekun AR, Gilger MA, Estes MK, Crawford SE, Neill FH, Graham DY | title = Norwalk Virus Shedding after Experimental Human Infection | journal = Emerging Infect. Dis. | volume = 14 | issue = 10 | pages = 1553–7 | date = October 2008 | pmid = 18826818 | pmc = 2609865 | doi = 10.3201/eid1410.080117 |name-list-format=vanc  }}</ref>
Norovirus is transmitted through person-to-person contact, food and water. Genotype GII.4 is mostly contact transmitted. Non-GII.4 genotypes such as GI.3, GI.6, GI.7, GII.3, GII.6 and GII.12 are mostly food-borne. Genogroup GI strains are more often transmitted through water. This is due to their higher stability in water compared to other strains of the virus.<ref name="pmid27211790">{{cite journal| author=de Graaf M, van Beek J, Koopmans MP| title=Human norovirus transmission and evolution in a changing world. | journal=Nat Rev Microbiol | year= 2016 | volume= 14 | issue= 7 | pages= 421-33 | pmid=27211790 | doi=10.1038/nrmicro.2016.48 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27211790 }} </ref><ref name="pmid19494060">{{cite journal| author=Lysén M, Thorhagen M, Brytting M, Hjertqvist M, Andersson Y, Hedlund KO| title=Genetic diversity among food-borne and waterborne norovirus strains causing outbreaks in Sweden. | journal=J Clin Microbiol | year= 2009 | volume= 47 | issue= 8 | pages= 2411-8 | pmid=19494060 | doi=10.1128/JCM.02168-08 | pmc=2725682 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19494060 }} </ref>  
 
Norovirus is among top ranks of food born viruses, globally<ref name="pmid26633896">{{cite journal| author=Havelaar AH, Kirk MD, Torgerson PR, Gibb HJ, Hald T, Lake RJ | display-authors=etal| title=World Health Organization Global Estimates and Regional Comparisons of the Burden of Foodborne Disease in 2010. | journal=PLoS Med | year= 2015 | volume= 12 | issue= 12 | pages= e1001923 | pmid=26633896 | doi=10.1371/journal.pmed.1001923 | pmc=4668832 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26633896 }} </ref>. Transmission could occur in different stages of pre- and post-production of the food products. For instance, Shellfish can be contaminated with fecal discharge in the water, fresh and frozen berries could be contaminated through water contaminated by sewage or contact during harvesting. Viral outbreaks through food-borne transmission can lead to a mixture of the viral strain and increased risk of genetic recombination. Studies show that about 7% of the foodborne outbreaks have a common source. 
Vomiting, in particular, transmits infection effectively, and appears to allow airborne transmission. In one incident, a person who vomited spread infection right across a restaurant, suggesting that many unexplained cases of food poisoning may have their source in vomit.<ref>{{cite journal | author = Marks PJ, Vipond IB, Carlisle D, Deakin D, Fey RE, Caul EO | title = Evidence for airborne transmission of Norwalk-like virus (NLV) in a hotel restaurant | journal = Epidemiol. Infect. | volume = 124 | issue = 3 | pages = 481–487 | date = June 2000 | pmid = 10982072 | pmc = 2810934 | doi = 10.1017/s0950268899003805 | url = http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=54261 }}</ref> 126 people were dining at six tables in December 1998; one woman vomited onto the floor. Staff quickly cleaned up, and people continued eating. Three days later others started falling ill; 52 people reported a range of symptoms, from fever and nausea to vomiting and diarrhea. The cause was not immediately identified. Researchers plotted the seating arrangement: more than 90% of the people at the same table as the sick woman later reported becoming ill. There was a direct correlation between the risk of infection of people at other tables and how close they were to the sick woman. More than 70% of the diners at an adjacent table fell ill; at a table on the other side of the restaurant, the attack rate was still 25%. The outbreak was attributed to a Norwalk-like virus (norovirus). Other cases of transmission by vomit were later identified.<ref>{{cite journal | author = Marks PJ, Vipond IB, Regan FM, Wedgwood K, Fey RE, Caul EO | title = A school outbreak of Norwalk-like virus: evidence for airborne transmission | journal = Epidemiol. Infect. | volume = 131 | issue = 1 | pages = 727–736 | date = Aug 2003 | pmid = 12948373 | pmc = 2870014 | doi = 10.1017/s0950268803008689 | url = http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=177137 }}</ref>
Norovirus also has a nosocomial transition, causing a major burden for health care services. Immunocompromised patients may develop numerous norovirus variations due to the chronic infection. This intra-host viral variation may lead to the appearance of variants not similar to any of the ones of previous outbreaks, thus can escape the herd immunity.<ref name="pmid27211790">{{cite journal| author=de Graaf M, van Beek J, Koopmans MP| title=Human norovirus transmission and evolution in a changing world. | journal=Nat Rev Microbiol | year= 2016 | volume= 14 | issue= 7 | pages= 421-33 | pmid=27211790 | doi=10.1038/nrmicro.2016.48 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27211790  }} </ref>
 
To date, animal norovirus strains have not been reported to infect human population, but there has been evidence of intra-species transmission. Human norovirus has been detected in the stools of pigs, cattle and dogs.<ref name="pmid27211790">{{cite journal| author=de Graaf M, van Beek J, Koopmans MP| title=Human norovirus transmission and evolution in a changing world. | journal=Nat Rev Microbiol | year= 2016 | volume= 14 | issue= 7 | pages= 421-33 | pmid=27211790 | doi=10.1038/nrmicro.2016.48 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27211790  }} </ref>
In one outbreak at an international scout jamboree in the Netherlands, each person with gastroenteritis infected an average of 14 people before increased hygiene measures were put in place. Even after these new measures were enacted, an ill person still infected an average of 2.1 other people.<ref>{{cite journal | author = Heijne JC, Teunis P, Morroy G, Wijkmans C, Oostveen S, Duizer E, Kretzschmar M, Wallinga J | title = Enhanced Hygiene Measures and Norovirus Transmission during an Outbreak | journal = Emerg. Infect. Dis. | volume = 15 | issue = 1 | pages = 24–30 | year = 2009 | pmid = 19116045 | pmc = 2660689 | doi = 10.3201/1501.080299 | url = http://www.cdc.gov/EID/content/15/1/pdfs/24.pdf |name-list-format=vanc }}</ref> A [[Centers for Disease Control and Prevention|CDC]] study of 11 outbreaks in New York State lists the suspected [[Transmission (medicine)|mode of transmission]] as person-to-person in seven outbreaks, foodborne in two, waterborne in one, and one unknown. The source of waterborne outbreaks may include water from municipal supplies, wells, recreational lakes, swimming pools and ice machines.<ref name="pmid8395330">{{cite journal | author = Hedberg CW, Osterholm MT | title = Outbreaks of food-borne and waterborne viral gastroenteritis | journal = Clin. Microbiol. Rev. | volume = 6 | issue = 3 | pages = 199–210 | year = 1993 | pmid = 8395330 | pmc = 358282 | doi =  | url = http://cmr.asm.org/cgi/pmidlookup?view=long&pmid=8395330 }}</ref>
 
[[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.<ref>[http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/Norovirus/oysterconsumptionnorovirus/ Shellfish consumption and the risk of norovirus infection]</ref> Foods other than shellfish may be contaminated by infected food handlers.<ref name="pmid11479930">{{cite journal | author = Parashar UD, Monroe SS | title = "Norwalk-like viruses" as a cause of foodborne disease outbreaks | journal = Rev. Med. Virol. | volume = 11 | issue = 4 | pages = 243–52 | year = 2001 | pmid = 11479930 | doi = 10.1002/rmv.321 }}</ref>


=== Classification ===
=== Classification ===

Revision as of 17:17, 1 January 2021

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This page is about microbiologic aspects of the organism(s).  For clinical aspects of the disease, see Norovirus infection.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Norovirus is the cause of norovirus infection. Noroviruses (genus Norovirus) are a group of related, single-stranded RNA, nonenveloped viruses that cause acute gastroenteritis in humans. Noroviruses belong to the family Caliciviridae.

Norovirus

Norovirus was the first virus to present with gastroenteritis in human and was first identified from stool specimen[1]. The illness caused by this virus was primarily given the term “winter vomiting disease”, due to its prominent gastrointestinal manifestations[2]. An outbreak in 1968 at an elementary school in Norwalk lead to the identification of the virus. Norovirus is the leading cause of gastroenteritis among all age groups and is responsible for 64000 cases of diarrhea leading to hospitalization, 900,000 visits to the clinic among children of developed countries and 200,000 deaths among children below 5 in developing countries[3][4].

Virology

Transmission

Norovirus is transmitted through person-to-person contact, food and water. Genotype GII.4 is mostly contact transmitted. Non-GII.4 genotypes such as GI.3, GI.6, GI.7, GII.3, GII.6 and GII.12 are mostly food-borne. Genogroup GI strains are more often transmitted through water. This is due to their higher stability in water compared to other strains of the virus.[5][6] Norovirus is among top ranks of food born viruses, globally[7]. Transmission could occur in different stages of pre- and post-production of the food products. For instance, Shellfish can be contaminated with fecal discharge in the water, fresh and frozen berries could be contaminated through water contaminated by sewage or contact during harvesting. Viral outbreaks through food-borne transmission can lead to a mixture of the viral strain and increased risk of genetic recombination. Studies show that about 7% of the foodborne outbreaks have a common source. Norovirus also has a nosocomial transition, causing a major burden for health care services. Immunocompromised patients may develop numerous norovirus variations due to the chronic infection. This intra-host viral variation may lead to the appearance of variants not similar to any of the ones of previous outbreaks, thus can escape the herd immunity.[5] To date, animal norovirus strains have not been reported to infect human population, but there has been evidence of intra-species transmission. Human norovirus has been detected in the stools of pigs, cattle and dogs.[5]

Classification

Noroviruses (NoV) are a genetically diverse group of single-stranded RNA, non-enveloped viruses belonging to the Caliciviridae family.[8] According to the International Committee on Taxonomy of Viruses, the genus Norovirus has one species, which is called Norwalk virus.[9]

Noroviruses commonly isolated in cases of acute gastroenteritis belong to two genogroups: genogroup I (GI) includes Norwalk virus, Desert Shield virus and Southampton virus; and II (GII), which includes Bristol virus, Lordsdale virus, Toronto virus, Mexico virus, Hawaii virus and Snow Mountain virus.[8]

Noroviruses can genetically be classified into five different genogroups (GI, GII, GIII, GIV, and GV), which can be further divided into different genetic clusters or genotypes. For example, genogroup II, the most prevalent human genogroup, presently contains 19 genotypes. Genogroups I, II and IV infect humans, whereas genogroup III infects bovine species, and genogroup V has recently been isolated in mice.[10]

Most noroviruses that infect humans belong to genogroups GI and GII.[11] Noroviruses from Genogroup II, genotype 4 (abbreviated as GII.4) account for the majority of adult outbreaks of gastroenteritis and often sweep across the globe.[12] Recent examples include US95/96-US strain, associated with global outbreaks in the mid- to late-1990s; Farmington Hills virus associated with outbreaks in Europe and the United States in 2002 and in 2004; and Hunter virus which was associated with outbreaks in Europe, Japan and Australasia. In 2006, there was another large increase in NoV infection around the globe.[13] 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.[14]

A 2008 study suggests the protein MDA-5 may be the primary immune sensor that detects the presence of noroviruses in the body.[15] Some people have common variations of the MDA-5 gene that could make them more susceptible to norovirus infection.[16]

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).

Structure

Viruses in Norovirus are non-enveloped, with icosahedral geometries. Capsid diameters vary widely, from 23-40 nm in diameter. The larger capsids (38-40 nm) exhibit T=3 symmetry and are composed of 180 VP1 proteins. Small capsids (23 nm) show T=1 symmetry, and are composed of 60 VP1 proteins.[17] The virus particles demonstrate an amorphous surface structure when visualized using electron microscopy.[18]

Noroviruses contain a linear, non-segmented,[17] positive-sense RNA genome of approximately 7.5kbp, encoding a major structural protein (VP1) of about 58~60 kDa and a minor capsid protein (VP2).[19]

The most variable region of the viral capsid is the P2 domain, which contains antigen-presenting sites and carbohydrate-receptor binding regions.[20][21][22][23]

The estimated mutation rate (1.21Template:E to 1.41 Template:E substitutions per site per year) in this virus is high even compared with other RNA viruses.[24]

Genus Structure Symmetry Capsid Genomic Arrangement Genomic Segmentation
Norovirus Icosahedral T=1, T=3 Non-Enveloped Linear Monopartite

Life Cycle

Viral replication is cytoplasmic. Entry into the host cell is achieved by attachment to host receptors, which mediates endocytosis. Replication follows the positive stranded RNA virus replication model. Positive stranded RNA virus transcription is the method of transcription. Translation takes place by leaky scanning, and RNA termination-reinitiation. Human and mammals serve as the natural host. Transmission routes are fecal-oral and contamination.[17]

Genus Host Details Tissue Tropism Entry Details Release Details Replication Site Assembly Site Transmission
Norovirus Humans; mammals Intestinal epithelium Cell receptor endocytosis Lysis Cytoplasm Cytoplasm Oral-fecal

Gallery

References

  1. ↑ Kapikian AZ, Wyatt RG, Dolin R, Thornhill TS, Kalica AR, Chanock RM (1972). "Visualization by immune electron microscopy of a 27-nm particle associated with acute infectious nonbacterial gastroenteritis". J Virol. 10 (5): 1075–81. doi:10.1128/JVI.10.5.1075-1081.1972. PMC 356579. PMID 4117963.
  2. ↑ Lopman BA, Reacher M, Gallimore C, Adak GK, Gray JJ, Brown DW (2003). "A summertime peak of "winter vomiting disease": surveillance of noroviruses in England and Wales, 1995 to 2002". BMC Public Health. 3: 13. doi:10.1186/1471-2458-3-13. PMC 153520. PMID 12659651.
  3. ↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID .3201/eid1408.071114. 10 .3201/eid1408.071114. Check |pmid= value (help).
  4. ↑ Robilotti E, Deresinski S, Pinsky BA (2015). "Norovirus". Clin Microbiol Rev. 28 (1): 134–64. doi:10.1128/CMR.00075-14. PMC 4284304. PMID 25567225.
  5. ↑ 5.0 5.1 5.2 de Graaf M, van Beek J, Koopmans MP (2016). "Human norovirus transmission and evolution in a changing world". Nat Rev Microbiol. 14 (7): 421–33. doi:10.1038/nrmicro.2016.48. PMID 27211790.
  6. ↑ Lysén M, Thorhagen M, Brytting M, Hjertqvist M, Andersson Y, Hedlund KO (2009). "Genetic diversity among food-borne and waterborne norovirus strains causing outbreaks in Sweden". J Clin Microbiol. 47 (8): 2411–8. doi:10.1128/JCM.02168-08. PMC 2725682. PMID 19494060.
  7. ↑ Havelaar AH, Kirk MD, Torgerson PR, Gibb HJ, Hald T, Lake RJ; et al. (2015). "World Health Organization Global Estimates and Regional Comparisons of the Burden of Foodborne Disease in 2010". PLoS Med. 12 (12): e1001923. doi:10.1371/journal.pmed.1001923. PMC 4668832. PMID 26633896.
  8. ↑ 8.0 8.1 Department of Health and Ageing Norovirus laboratory case definition
  9. ↑ Eric B. Carstens; King, Andrew; Elliot Lefkowitz; Adams, Michael Ian (2011). Virus Taxonomy: Ninth Report of the International Committee on Taxonomy of Viruses. Amsterdam: Elsevier. pp. 981–982. ISBN 0-12-384684-6.
  10. ↑ Ramirez S, Giammanco GM, De Grazia S, Colomba C, Martella V, Arista S (2008). "Genotyping of GII.4 and GIIb norovirus RT-PCR amplicons by RFLP analysis". J. Virol. Methods. 147 (2): 250–6. doi:10.1016/j.jviromet.2007.09.005. PMID 17953996.
  11. ↑ Vinjé J, Green J, Lewis DC, Gallimore CI, Brown DW, Koopmans MP (2000). "Genetic polymorphism across regions of the three open reading frames of "Norwalk-like viruses"". Arch. Virol. 145 (2): 223–41. doi:10.1007/s007050050020. PMID 10752550.
  12. ↑ Noel JS, Fankhauser RL, Ando T, Monroe SS, Glass RI (2000). "Identification of a distinct common strain of "Norwalk-like viruses" having a global distribution". J. Infect. Dis. 179 (6): 1334–44. doi:10.1086/314783. PMID 10228052.
  13. ↑ Tu ET, Bull RA, Greening GE, Hewitt J, Lyon MJ, Marshall JA, McIver CJ, Rawlinson WD, White PA (2008). "Epidemics of gastroenteritis during 2006 were associated with the spread of norovirus GII.4 variants 2006a and 2006b". Clin. Infect. Dis. 46 (3): 413–20. doi:10.1086/525259. PMID 18177226.
  14. ↑ Shirato H (2011). "Norovirus and histo-blood group antigens". Japanese Journal of Infectious Diseases. 64 (2): 95–103. PMID 21519121.
  15. ↑ McCartney SA, Thackray LB, Gitlin L, Gilfillan S, Virgin HW, 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.
  16. ↑ Researchers Discover Primary Sensor That Detects Stomach Viruses Newswise, Retrieved on July 20, 2008.
  17. ↑ 17.0 17.1 17.2 "Viral Zone". ExPASy. Retrieved 15 June 2015.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ Tan M, Hegde RS, Jiang X (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.
  21. ↑ 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.
  22. ↑ Cao S, Lou Z, Tan M, Chen Y, Liu Y, Zhang Z, Zhang XC, Jiang X, Li X, Rao Z (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.
  23. ↑ Lundborg M, Ali E, Widmalm G (2013). "An in silico virtual screening study for the design of norovirus inhibitors: fragment-based molecular docking and binding free energy calculations". Carbohydr Res. 378: 133–8. doi:10.1016/j.carres.2013.03.012. PMID 23582100.
  24. ↑ 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. doi:10.1016/j.meegid.2009.06.014. PMID 19559104.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 "Public Health Image Library (PHIL)".


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