Norovirus infection pathophysiology: Difference between revisions

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== Overview ==
==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]].
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==
==Pathophysiology==
=== Physiology ===
===Physiology===
*Noroviruses contain a [[Sense (molecular biology)|positive-sense]] [[RNA]] [[genome]] of approximately 7.5 [[Base pair#Length measurements|kbp]], encoding a major structural [[protein]] (VP1) of about 58~60 [[kDa]] and a minor [[capsid]] protein (VP2).<ref name="pmid10804143">{{cite journal
====Structure====
|author=Clarke IN, Lambden PR
 
|title=Organization and expression of calicivirus genes
*Norovirus [[genome]] structure and protein coding regions: the genome is [[positive-sense]] [[single stranded]] [[RNA]] encoding three [[open reading frames]] (ORF). [[ORF1]] encodes the nonstructural proteins. ORF2 and ORF3 encode the major capsid (VP1) and minor structural protein (VP2), respectively.<ref name="pmid16168575">{{cite journal| author=Hardy ME| title=Norovirus protein structure and function. | journal=FEMS Microbiol Lett | year= 2005 | volume= 253 | issue= 1 | pages= 1-8 | pmid=16168575 | doi=10.1016/j.femsle.2005.08.031 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16168575  }} </ref>
|journal=J. Infect. Dis.
*Structural proteins: Norovirus consists of 90 dimers of VP1 and one or two copies of the VP2.
|volume=181 Suppl 2
**VP1: This major structural protein encoded by ORF2, consists of 530–555 amino acids with calculated molecular weights of 58–60 kDa. The protein has two conserved domains and a central variable domain with antigenic characteristics defining the specificity of the strain. VP1 assembles into virus-like particles<ref name="pmid11907243">{{cite journal| author=Bertolotti-Ciarlet A, White LJ, Chen R, Prasad BV, Estes MK| title=Structural requirements for the assembly of Norwalk virus-like particles. | journal=J Virol | year= 2002 | volume= 76 | issue= 8 | pages= 4044-55 | pmid=11907243 | doi=10.1128/jvi.76.8.4044-4055.2002 | pmc=136079 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11907243  }} </ref>. VP1 has two major domains; 1) the shell domain (S) and 2) the protruding domain (P). The S domain is on the N-terminal (225 amino acids), containing the elements for icosahedron formation<ref name="pmid10514371">{{cite journal| author=Prasad BV, Hardy ME, Dokland T, Bella J, Rossmann MG, Estes MK| title=X-ray crystallographic structure of the Norwalk virus capsid. | journal=Science | year= 1999 | volume= 286 | issue= 5438 | pages= 287-90 | pmid=10514371 | doi=10.1126/science.286.5438.287 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10514371  }} </ref>. The P domain is comprised of the remaining amino acids and has two subdomains of P1 and P2.  The P domain contributes to the stability of the capsid and formation of protrusions on the virion. P2 has a hypervariable region which is thought to play a role in receptor binding, immune reaction and interactions of ABO blood group antigens associated with susceptibility to the [[viral infection]].<ref name="pmid14610179">{{cite journal| author=Tan M, Huang P, Meller J, Zhong W, Farkas T, Jiang X| title=Mutations within the P2 domain of norovirus capsid affect binding to human histo-blood group antigens: evidence for a binding pocket. | journal=J Virol | year= 2003 | volume= 77 | issue= 23 | pages= 12562-71 | pmid=14610179 | doi=10.1128/jvi.77.23.12562-12571.2003 | pmc=262557 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14610179  }} </ref><ref name="pmid16168575">{{cite journal| author=Hardy ME| title=Norovirus protein structure and function. | journal=FEMS Microbiol Lett | year= 2005 | volume= 253 | issue= 1 | pages= 1-8 | pmid=16168575 | doi=10.1016/j.femsle.2005.08.031 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16168575  }} </ref>
|issue=
**VP2: This minor structural protein encoded by ORF3, ranges from 208–268 amino acids with calculated molecular weights of 22–29 kDa. VP2 shows high sequence diversity among strains. The exact function of this protein in the virus is not yet known. It is suggested that VP2 might contribute in RNA genome packaging. VP2 is not necessary for viral particles assembly but it is necessary for the formation of an infection virus. <ref name="pmid16168575">{{cite journal| author=Hardy ME| title=Norovirus protein structure and function. | journal=FEMS Microbiol Lett | year= 2005 | volume= 253 | issue= 1 | pages= 1-8 | pmid=16168575 | doi=10.1016/j.femsle.2005.08.031 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16168575  }} </ref>
|pages=S309–16
*Nonstructural proteins<ref name="pmid16168575">{{cite journal| author=Hardy ME| title=Norovirus protein structure and function. | journal=FEMS Microbiol Lett | year= 2005 | volume= 253 | issue= 1 | pages= 1-8 | pmid=16168575 | doi=10.1016/j.femsle.2005.08.031 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16168575  }} </ref>
|year=2000
**p48 (p37)
|pmid=10804143
**p22 (p20)
|doi=10.1086/315575
**VPg
|url=http://www.journals.uchicago.edu/cgi-bin/resolve?JID990679
**3CLpro
}}</ref>  
**RdRp
*The virus particles demonstrate an amorphous surface structure when visualized using [[electron microscopy]] and are between 27-38 [[Meter#SI prefixed forms of metre|nm]] in size.<ref name="pmid11444031">{{cite journal
 
|author=Prasad BV, Crawford S, Lawton JA, Pesavento J, Hardy M, Estes MK
====Life Cycle====
|title=Structural studies on gastroenteritis viruses
Norovirus has a cytoplasmic replication. It attaches to the host receptors and enters the cell through endocytosis. Since, it is a positive sense virus, [[replication]] and [[Transcription (genetics)|transcription]] follows the corresponding models for positive stranded RNA viruses. [[Translation (genetics)|Translation]] occurs by leaky scanning, and RNA termination-reinitiation.<ref name="ViralZone" />
|journal=Novartis Found. Symp.
 
|volume=238
{| class="wikitable sortable" style="text-align:center"
|issue=
|-
|pages=26–37; discussion 37–46
!Genus!!Host Details!!Tissue Tropism!!Entry Details!!Release Details!!Replication Site!!Assembly Site!!Transmission
|year=2001
|-
|pmid=11444031
|Norovirus||Humans; mammals||Intestinal epithelium||Cell receptor endocytosis||Lysis||Cytoplasm||Cytoplasm||Oral-fecal
|doi=10.1002/0470846534.ch3
|}
|series=Novartis Foundation Symposia
|isbn=978-0-470-84653-7
}}</ref>
*The most variable region of the viral capsid is the P2 domain, which contains antigen-presenting sites and carbohydrate-receptor binding regions.<ref>{{cite journal
|author=Jiang X, Tan M, Hegde RS
|title=The P Domain of Norovirus Capsid Protein Forms Dimer and Binds to Histo-Blood Group Antigen Receptors
|journal=J. Virol.
|volume=78
|issue=12
|pages=6233–42
|year=2004
|doi=10.1128/JVI.78.12.6233-6242.2004
|pmid=15163716
|pmc=416535}}</ref><ref>{{cite journal
|author=Tan M, Huang PW, Meller J, Zhong WM, Farkas T, Jiang X
|title=Mutations within the P2 domain of norovirus capsid affect binding to human histo-blood group antigens: evidence for a binding pocket
|journal=J. Virol.
|volume=78
|issue=6
|page=3201
|year=2004
|doi=10.1128/JVI.78.6.3201.2004}}</ref><ref>{{cite journal
|author=Cao S, Lou ZY, Tan M, Chen YT, Liu YJ, Zhang ZS, Zhang XJC
|title=Structural Basis for the Recognition of Blood Group Trisaccharides by Norovirus
|journal=J. Virol.
|volume=81
|issue=11
|pages=5949–57
|year=2007
|doi=10.1128/JVI.00219-07
|pmid=17392366
|pmc=1900264}}</ref>
*The estimated mutation rate (1.21 x 10<sup>−2</sup> to 1.41 x 10<sup>−2</sup> substitutions per site per year) in this virus is high even compared with other RNA viruses.<ref name=Victoria2009>{{cite journal | author = Victoria M, Miagostovich MP, Ferreira MS, Vieira CB, Fioretti JM, Leite JP, Colina R, Cristina J | year = 2009 | title = Bayesian coalescent inference reveals high evolutionary rates and expansion of Norovirus populations | url = | journal = Infect Genet Evol | volume = 9 | issue = 5| pages = 927–932 }}</ref>


===Pathogenesis===
===Pathogenesis===
Noroviruses are highly transmissible since only 10 virions (ID50 = 10 virions) per individual is required to infect half proportion of those individuals. Norovirus is transmitted via aerosols, direct contact and fecal-oral routes. The virus is highly resistant to extremely low and/or high temperatures, high sugar concentrations, acidic environments, exposure to chlorine, antiseptic solutions and alcohol. The virus has an incubation period of about 1-2 days with symptoms lasting for about 1-3 days. It could remain contagious for up to 3 weeks.
Noroviruses are highly transmissible since only 10 [[virions]] (ID50 = 10 virions) per individual is required to infect half proportion of those individuals. Norovirus is transmitted via [[aerosols]], [[direct contact]] and [[Fecal-oral route|fecal-oral]] routes. The virus is highly resistant to extremely low and/or high temperatures, high sugar concentrations, [[acidic]] environments, exposure to [[chlorine]], [[antiseptic]] solutions and alcohol. The virus has an [[incubation period]] of about 1-2 days with symptoms lasting for about 1-3 days. It could remain [[contagious]] for up to 3 weeks.<ref name="pmid18837783">{{cite journal| author=Donaldson EF, Lindesmith LC, Lobue AD, Baric RS| title=Norovirus pathogenesis: mechanisms of persistence and immune evasion in human populations. | journal=Immunol Rev | year= 2008 | volume= 225 | issue=  | pages= 190-211 | pmid=18837783 | doi=10.1111/j.1600-065X.2008.00680.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18837783  }} </ref> Histoblood group [[antigens]] (HBGAs) are polymorphic [[receptors]] or [[cofactors]] of norovirus. Different genoclusters bind various HBGAs: [[Genogroup]] I viruses bind A and O antigens; genogroup II viruses mostly bind A and B antigens.  Great diversity of norovirus strains and the lack of cross-strain or long-term immunity are the causes of recurrent infections.<ref name="pmid12825167">{{cite journal| author=Huang P, Farkas T, Marionneau S, Zhong W, Ruvoën-Clouet N, Morrow AL | display-authors=etal| title=Noroviruses bind to human ABO, Lewis, and secretor histo-blood group antigens: identification of 4 distinct strain-specific patterns. | journal=J Infect Dis | year= 2003 | volume= 188 | issue= 1 | pages= 19-31 | pmid=12825167 | doi=10.1086/375742 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12825167  }} </ref>
The virus primarily damages the [[microvilli]] of the cells of the small intestine.<ref name="pmid4706274">{{cite journal| author=Schreiber DS, Blacklow NR, Trier JS| title=The mucosal lesion of the proximal small intestine in acute infectious nonbacterial gastroenteritis. | journal=N Engl J Med | year= 1973 | volume= 288 | issue= 25 | pages= 1318-23 | pmid=4706274 | doi=10.1056/NEJM197306212882503 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4706274  }} </ref> It affects the motility of stomach leading to delayed [[gastric emptying]] and eventually [[nausea and vomiting]].<ref name="pmid1089575">{{cite journal| author=Widerlite L, Trier JS, Blacklow NR, Schreiber DS| title=Structure of the gastric mucosa in acute infectious bacterial gastroenteritis. | journal=Gastroenterology | year= 1975 | volume= 68 | issue= 3 | pages= 425-30 | pmid=1089575 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1089575  }} </ref>The virus is responsible for the enzymatic disorder, leak flux, anion secretion and fat [[malabsorption]] at the [[brush border]] leading to [[diarrhea]] in infected individuals. [[Colon (anatomy)|Colon]] is intact in this infection so [[hematochezia]] is rare.<ref name="pmid19036950">{{cite journal| author=Troeger H, Loddenkemper C, Schneider T, Schreier E, Epple HJ, Zeitz M | display-authors=etal| title=Structural and functional changes of the duodenum in human norovirus infection. | journal=Gut | year= 2009 | volume= 58 | issue= 8 | pages= 1070-7 | pmid=19036950 | doi=10.1136/gut.2008.160150 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19036950  }} </ref><ref name="pmid4554885">{{cite journal| author=| title=Acute infectious nonbacterial gastroenteritis: etiology and pathogenesis. | journal=Ann Intern Med | year= 1972 | volume= 76 | issue= 6 | pages= 993-1008 | pmid=4554885 | doi=10.7326/0003-4819-76-6-993 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4554885  }} </ref>


==Genetics==
==Genetics==
*A non-functional [[fucosyltransferase]] FUT2 provides high protection from the most common norovirus GII.4.<ref name="pmid19440360">{{cite journal| author=Carlsson B, Kindberg E, Buesa J, Rydell GE, Lidón MF, Montava R | display-authors=etal| title=The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection. | journal=PLoS One | year= 2009 | volume= 4 | issue= 5 | pages= e5593 | pmid=19440360 | doi=10.1371/journal.pone.0005593 | pmc=2680586 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19440360  }} </ref>
*A non-functional [[fucosyltransferase]] FUT2 provides high protection from the most common norovirus GII.4.<ref name="pmid19440360">{{cite journal| author=Carlsson B, Kindberg E, Buesa J, Rydell GE, Lidón MF, Montava R | display-authors=etal| title=The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection. | journal=PLoS One | year= 2009 | volume= 4 | issue= 5 | pages= e5593 | pmid=19440360 | doi=10.1371/journal.pone.0005593 | pmc=2680586 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19440360  }} </ref>
*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.  
*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.<ref name="pmid22025362">{{cite journal| author=Rydell GE, Kindberg E, Larson G, Svensson L| title=Susceptibility to winter vomiting disease: a sweet matter. | journal=Rev Med Virol | year= 2011 | volume= 21 | issue= 6 | pages= 370-82 | pmid=22025362 | doi=10.1002/rmv.704 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22025362  }} </ref>
*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.<ref name="pmid22025362">{{cite journal| author=Rydell GE, Kindberg E, Larson G, Svensson L| title=Susceptibility to winter vomiting disease: a sweet matter. | journal=Rev Med Virol | year= 2011 | volume= 21 | issue= 6 | pages= 370-82 | pmid=22025362 | doi=10.1002/rmv.704 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22025362  }} </ref>
*Non-secretors can still produce ABH antigens in erythrocytes as the precursor is formed by FUT1.<ref>{{cite journal |author=Shirato H |title=Norovirus and histo-blood group antigens |journal=Jpn. J. Infect. Dis. |volume=64 |issue=2 |pages=95–103 |year=2011 |pmid=21519121 |doi= |url=}}</ref> Some norovirus genotypes (GI.3) can infect non-secretors.<ref name="pmid20031047">{{cite journal| author=Nordgren J, Kindberg E, Lindgren PE, Matussek A, Svensson L| title=Norovirus gastroenteritis outbreak with a secretor-independent susceptibility pattern, Sweden. | journal=Emerg Infect Dis | year= 2010 | volume= 16 | issue= 1 | pages= 81-7 | pmid=20031047 | doi=10.3201/eid1601.090633 | pmc=2874438 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20031047  }} </ref>
*Non-secretors can still produce ABH antigens in erythrocytes as the precursor is formed by FUT1.<ref>{{cite journal |author=Shirato H |title=Norovirus and histo-blood group antigens |journal=Jpn. J. Infect. Dis. |volume=64 |issue=2 |pages=95–103 |year=2011 |pmid=21519121 |doi= |url=}}</ref> Some norovirus genotypes (GI.3) can infect non-secretors.<ref name="pmid20031047">{{cite journal| author=Nordgren J, Kindberg E, Lindgren PE, Matussek A, Svensson L| title=Norovirus gastroenteritis outbreak with a secretor-independent susceptibility pattern, Sweden. | journal=Emerg Infect Dis | year= 2010 | volume= 16 | issue= 1 | pages= 81-7 | pmid=20031047 | doi=10.3201/eid1601.090633 | pmc=2874438 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20031047  }} </ref>
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*A 2008 study suggests the protein [[IFIH1|MDA-5]] may be the primary immune sensor that detects the presence of noroviruses in the body.<ref name="pmid18636103">{{cite journal| author=McCartney SA, Thackray LB, Gitlin L, Gilfillan S, Virgin HW, Virgin Iv HW | display-authors=etal| title=MDA-5 recognition of a murine norovirus. | journal=PLoS Pathog | year= 2008 | volume= 4 | issue= 7 | pages= e1000108 | pmid=18636103 | doi=10.1371/journal.ppat.1000108 | pmc=2443291 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18636103  }} </ref>  Interestingly, some people have common variations of the MDA-5 gene that could make them more susceptible to norovirus infection.<ref>[http://newswise.com/articles/view/542714/ Researchers Discover Primary Sensor That Detects Stomach Viruses] Newswise, Retrieved on July 20, 2008.</ref>
*A 2008 study suggests the protein [[IFIH1|MDA-5]] may be the primary immune sensor that detects the presence of noroviruses in the body.<ref name="pmid18636103">{{cite journal| author=McCartney SA, Thackray LB, Gitlin L, Gilfillan S, Virgin HW, Virgin Iv HW | display-authors=etal| title=MDA-5 recognition of a murine norovirus. | journal=PLoS Pathog | year= 2008 | volume= 4 | issue= 7 | pages= e1000108 | pmid=18636103 | doi=10.1371/journal.ppat.1000108 | pmc=2443291 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18636103  }} </ref>  Interestingly, some people have common variations of the MDA-5 gene that could make them more susceptible to norovirus infection.<ref>[http://newswise.com/articles/view/542714/ Researchers Discover Primary Sensor That Detects Stomach Viruses] Newswise, Retrieved on July 20, 2008.</ref>
*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).
*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).
==Associated Conditions==
==Associated Conditions==
Conditions associated with Norovirus infection include:<ref name="pmid25567225">{{cite journal| author=Robilotti E, Deresinski S, Pinsky BA| title=Norovirus. | journal=Clin Microbiol Rev | year= 2015 | volume= 28 | issue= 1 | pages= 134-64 | pmid=25567225 | doi=10.1128/CMR.00075-14 | pmc=4284304 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25567225  }} </ref>
*[[Immunocompromise]]
*[[Encephalopathy]]<ref name="pmid16804441">{{cite journal| author=Ito S, Takeshita S, Nezu A, Aihara Y, Usuku S, Noguchi Y | display-authors=etal| title=Norovirus-associated encephalopathy. | journal=Pediatr Infect Dis J | year= 2006 | volume= 25 | issue= 7 | pages= 651-2 | pmid=16804441 | doi=10.1097/01.inf.0000225789.92512.6d | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16804441  }} </ref>
*[[convulsions]]<ref name="pmid21309881">{{cite journal| author=Chan CM, Chan CW, Ma CK, Chan HB| title=Norovirus as cause of benign convulsion associated with gastro-enteritis. | journal=J Paediatr Child Health | year= 2011 | volume= 47 | issue= 6 | pages= 373-7 | pmid=21309881 | doi=10.1111/j.1440-1754.2010.01986.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21309881  }} </ref>
*[[Hematopoietic stem cell transplant]] recipients
*[[solid organ transplant]] recipients
==Gross Pathology==
==Gross Pathology==
On gross pathology, there are no characteristic features of norovirus.
==Microscopic Pathology==
==Microscopic Pathology==
In microscopic pathology, blunted villi are seen. The [[mucosa]] and [[epithelium]] are often intact.<ref name="pmid4706274">{{cite journal| author=Schreiber DS, Blacklow NR, Trier JS| title=The mucosal lesion of the proximal small intestine in acute infectious nonbacterial gastroenteritis. | journal=N Engl J Med | year= 1973 | volume= 288 | issue= 25 | pages= 1318-23 | pmid=4706274 | doi=10.1056/NEJM197306212882503 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4706274  }} </ref>Increased [[apoptosis]] and damage to [[tight junction]] proteins of the epithelial cells may be evident.<ref name="pmid19036950">{{cite journal| author=Troeger H, Loddenkemper C, Schneider T, Schreier E, Epple HJ, Zeitz M | display-authors=etal| title=Structural and functional changes of the duodenum in human norovirus infection. | journal=Gut | year= 2009 | volume= 58 | issue= 8 | pages= 1070-7 | pmid=19036950 | doi=10.1136/gut.2008.160150 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19036950  }} </ref>Gastric mucosa of the infected patients remains histopathologically intact.<ref name="pmid1089575">{{cite journal| author=Widerlite L, Trier JS, Blacklow NR, Schreiber DS| title=Structure of the gastric mucosa in acute infectious bacterial gastroenteritis. | journal=Gastroenterology | year= 1975 | volume= 68 | issue= 3 | pages= 425-30 | pmid=1089575 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1089575  }} </ref>
==Gallery==
<gallery>
File:Norovirus07.jpeg| Electron micrograph of the Norovirus. <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name="PHIL"> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>
File:Norovirus06.jpeg| Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name="PHIL"> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>
File:Norovirus05.jpeg| Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name="PHIL"> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>
File:Norovirus04.jpeg| Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name="PHIL"> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>
File:Norovirus03.jpeg| Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name="PHIL"> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>
File:Norovirus02.jpeg| Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name="PHIL"> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>
File:Norovirus01.jpeg| Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name="PHIL"> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>
</gallery>


== References ==
==References==
{{Reflist|2}}
{{Reflist|2}}


Latest revision as of 17:24, 8 March 2021

Norovirus infection Microchapters

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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

Physiology

Structure

  • Norovirus genome structure and protein coding regions: the genome is positive-sense single stranded RNA encoding three open reading frames (ORF). ORF1 encodes the nonstructural proteins. ORF2 and ORF3 encode the major capsid (VP1) and minor structural protein (VP2), respectively.[1]
  • Structural proteins: Norovirus consists of 90 dimers of VP1 and one or two copies of the VP2.
    • VP1: This major structural protein encoded by ORF2, consists of 530–555 amino acids with calculated molecular weights of 58–60 kDa. The protein has two conserved domains and a central variable domain with antigenic characteristics defining the specificity of the strain. VP1 assembles into virus-like particles[2]. VP1 has two major domains; 1) the shell domain (S) and 2) the protruding domain (P). The S domain is on the N-terminal (225 amino acids), containing the elements for icosahedron formation[3]. The P domain is comprised of the remaining amino acids and has two subdomains of P1 and P2. The P domain contributes to the stability of the capsid and formation of protrusions on the virion. P2 has a hypervariable region which is thought to play a role in receptor binding, immune reaction and interactions of ABO blood group antigens associated with susceptibility to the viral infection.[4][1]
    • VP2: This minor structural protein encoded by ORF3, ranges from 208–268 amino acids with calculated molecular weights of 22–29 kDa. VP2 shows high sequence diversity among strains. The exact function of this protein in the virus is not yet known. It is suggested that VP2 might contribute in RNA genome packaging. VP2 is not necessary for viral particles assembly but it is necessary for the formation of an infection virus. [1]
  • Nonstructural proteins[1]
    • p48 (p37)
    • p22 (p20)
    • VPg
    • 3CLpro
    • RdRp

Life Cycle

Norovirus has a cytoplasmic replication. It attaches to the host receptors and enters the cell through endocytosis. Since, it is a positive sense virus, replication and transcription follows the corresponding models for positive stranded RNA viruses. Translation occurs by leaky scanning, and RNA termination-reinitiation.[5]

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

Pathogenesis

Noroviruses are highly transmissible since only 10 virions (ID50 = 10 virions) per individual is required to infect half proportion of those individuals. Norovirus is transmitted via aerosols, direct contact and fecal-oral routes. The virus is highly resistant to extremely low and/or high temperatures, high sugar concentrations, acidic environments, exposure to chlorine, antiseptic solutions and alcohol. The virus has an incubation period of about 1-2 days with symptoms lasting for about 1-3 days. It could remain contagious for up to 3 weeks.[6] Histoblood group antigens (HBGAs) are polymorphic receptors or cofactors of norovirus. Different genoclusters bind various HBGAs: Genogroup I viruses bind A and O antigens; genogroup II viruses mostly bind A and B antigens. Great diversity of norovirus strains and the lack of cross-strain or long-term immunity are the causes of recurrent infections.[7] The virus primarily damages the microvilli of the cells of the small intestine.[8] It affects the motility of stomach leading to delayed gastric emptying and eventually nausea and vomiting.[9]The virus is responsible for the enzymatic disorder, leak flux, anion secretion and fat malabsorption at the brush border leading to diarrhea in infected individuals. Colon is intact in this infection so hematochezia is rare.[10][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).

Associated Conditions

Conditions associated with Norovirus infection include:[22]

Gross Pathology

On gross pathology, there are no characteristic features of norovirus.

Microscopic Pathology

In microscopic pathology, blunted villi are seen. The mucosa and epithelium are often intact.[8]Increased apoptosis and damage to tight junction proteins of the epithelial cells may be evident.[10]Gastric mucosa of the infected patients remains histopathologically intact.[9]

Gallery

References

  1. ↑ 1.0 1.1 1.2 1.3 Hardy ME (2005). "Norovirus protein structure and function". FEMS Microbiol Lett. 253 (1): 1–8. doi:10.1016/j.femsle.2005.08.031. PMID 16168575.
  2. ↑ Bertolotti-Ciarlet A, White LJ, Chen R, Prasad BV, Estes MK (2002). "Structural requirements for the assembly of Norwalk virus-like particles". J Virol. 76 (8): 4044–55. doi:10.1128/jvi.76.8.4044-4055.2002. PMC 136079. PMID 11907243.
  3. ↑ Prasad BV, Hardy ME, Dokland T, Bella J, Rossmann MG, Estes MK (1999). "X-ray crystallographic structure of the Norwalk virus capsid". Science. 286 (5438): 287–90. doi:10.1126/science.286.5438.287. PMID 10514371.
  4. ↑ Tan M, Huang P, Meller J, Zhong W, Farkas T, Jiang X (2003). "Mutations within the P2 domain of norovirus capsid affect binding to human histo-blood group antigens: evidence for a binding pocket". J Virol. 77 (23): 12562–71. doi:10.1128/jvi.77.23.12562-12571.2003. PMC 262557. PMID 14610179.
  5. ↑
  6. ↑ Donaldson EF, Lindesmith LC, Lobue AD, Baric RS (2008). "Norovirus pathogenesis: mechanisms of persistence and immune evasion in human populations". Immunol Rev. 225: 190–211. doi:10.1111/j.1600-065X.2008.00680.x. PMID 18837783.
  7. ↑ Huang P, Farkas T, Marionneau S, Zhong W, Ruvoën-Clouet N, Morrow AL; et al. (2003). "Noroviruses bind to human ABO, Lewis, and secretor histo-blood group antigens: identification of 4 distinct strain-specific patterns". J Infect Dis. 188 (1): 19–31. doi:10.1086/375742. PMID 12825167.
  8. ↑ 8.0 8.1 Schreiber DS, Blacklow NR, Trier JS (1973). "The mucosal lesion of the proximal small intestine in acute infectious nonbacterial gastroenteritis". N Engl J Med. 288 (25): 1318–23. doi:10.1056/NEJM197306212882503. PMID 4706274.
  9. ↑ 9.0 9.1 Widerlite L, Trier JS, Blacklow NR, Schreiber DS (1975). "Structure of the gastric mucosa in acute infectious bacterial gastroenteritis". Gastroenterology. 68 (3): 425–30. PMID 1089575.
  10. ↑ 10.0 10.1 Troeger H, Loddenkemper C, Schneider T, Schreier E, Epple HJ, Zeitz M; et al. (2009). "Structural and functional changes of the duodenum in human norovirus infection". Gut. 58 (8): 1070–7. doi:10.1136/gut.2008.160150. PMID 19036950.
  11. ↑ "Acute infectious nonbacterial gastroenteritis: etiology and pathogenesis". Ann Intern Med. 76 (6): 993–1008. 1972. doi:10.7326/0003-4819-76-6-993. PMID 4554885.
  12. ↑ Carlsson B, Kindberg E, Buesa J, Rydell GE, Lidón MF, Montava R; et al. (2009). "The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection". PLoS One. 4 (5): e5593. doi:10.1371/journal.pone.0005593. PMC 2680586. PMID 19440360.
  13. ↑ 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.
  14. ↑ Shirato H (2011). "Norovirus and histo-blood group antigens". Jpn. J. Infect. Dis. 64 (2): 95–103. PMID 21519121.
  15. ↑ 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. PMC 2874438. PMID 20031047.
  16. ↑ "Norovirus and histo-blood group antigens". Retrieved 22 December 2012.
  17. ↑ Hennessy EP, Green AD, Connor MP, Darby R, MacDonald P (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.
  18. ↑ Le Guyader FS, Krol J, Ambert-Balay K, Ruvoen-Clouet N, Desaubliaux B, Parnaudeau S; et al. (2010). "Comprehensive analysis of a norovirus-associated gastroenteritis outbreak, from the environment to the consumer". J Clin Microbiol. 48 (3): 915–20. doi:10.1128/JCM.01664-09. PMC 2832421. PMID 20053852.
  19. ↑ Shirato H (2011). "Norovirus and histo-blood group antigens". Japanese Journal of Infectious Diseases. 64 (2): 95–103. PMID 21519121.
  20. ↑ McCartney SA, Thackray LB, Gitlin L, Gilfillan S, Virgin HW, Virgin Iv HW; et al. (2008). "MDA-5 recognition of a murine norovirus". PLoS Pathog. 4 (7): e1000108. doi:10.1371/journal.ppat.1000108. PMC 2443291. PMID 18636103.
  21. ↑ Researchers Discover Primary Sensor That Detects Stomach Viruses Newswise, Retrieved on July 20, 2008.
  22. ↑ 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.
  23. ↑ Ito S, Takeshita S, Nezu A, Aihara Y, Usuku S, Noguchi Y; et al. (2006). "Norovirus-associated encephalopathy". Pediatr Infect Dis J. 25 (7): 651–2. doi:10.1097/01.inf.0000225789.92512.6d. PMID 16804441.
  24. ↑ Chan CM, Chan CW, Ma CK, Chan HB (2011). "Norovirus as cause of benign convulsion associated with gastro-enteritis". J Paediatr Child Health. 47 (6): 373–7. doi:10.1111/j.1440-1754.2010.01986.x. PMID 21309881.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 "Public Health Image Library (PHIL)".


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