West nile virus pathophysiology: Difference between revisions

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{{West nile virus}}
{{West nile virus}}
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{{CMG}}; {{AE}} {{YD}}


==Overview==
==Overview==
The natural reservoir of West Nile virus (WNV) is birds, particularly species with high-level [[viremia]]. In contrast, viremia is relatively rare among infected humans, who are considered dead-end hosts of the virus. WNV is transmitted by bites of various species of mosquitoes. Following [[inoculation]], [[replication]] of the virus occurs in the [[Langerhans epidermal dendritic cell]]. Among immunocompetent hosts, the replication process is immediately followed by activation of the [[immune system]], including [[complement pathway]]s, and humoral and [[adaptive immune response]]s that act simultaneously to clear the infection. On the other hand, immunocompromised patients may suffer CNS dissemination and fatal outcomes due to the failure to activate proper immunological pathways. Finally, the role of genetics in WNV susceptibility is not fully understood; but mice models and a few human experiments have described [[genetic mutation]]s that may predispose individuals to worse clinical disease of WNV infections.


==Pathogenesis==
==West Nile virus life cycle==
===Transmission===
The West Nile virus has an enzootic life cycle, being primarily transmitted between some species of birds and different [[species]] of mosquito [[vector]]s.<ref name="CampbellMarfin2002">{{cite journal|last1=Campbell|first1=Grant L|last2=Marfin|first2=Anthony A|last3=Lanciotti|first3=Robert S|last4=Gubler|first4=Duane J|title=West Nile virus|journal=The Lancet Infectious Diseases|volume=2|issue=9|year=2002|pages=519–529|issn=14733099|doi=10.1016/S1473-3099(02)00368-7}}</ref>
The West Nile Virus is transmitted by the bite of a mosquito.  Its life-cycle is based on a "bird-mosquito-bird transmission".  Although the virus may have 65 species of mosquitos as natural hosts, only a few of those are capable of transmitting the virus among birds and humans.  Those responsible for the viral transmission belong to different families, depending of the region of the US:<ref name="pmid23860989">{{cite journal| author=Petersen LR, Brault AC, Nasci RS| title=West Nile virus: review of the literature. | journal=JAMA | year= 2013 | volume= 310 | issue= 3 | pages= 308-15 | pmid=23860989 | doi=10.1001/jama.2013.8042 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23860989  }} </ref>
[[image:WNV life cycle.png|600px|thumb|center|West Nile virus life cycle<SMALL><SMALL>''[http://www.cdc.gov  - Center for Disease Control and Prevention(CDC)]''<ref name="CDC">{{Cite web | title = Center for Disease Control and Prevention (CDC) | url = http://www.cdc.gov}}</ref></SMALL></SMALL>]]
* Northern half of the United States - ''Culex pipiens''
* Southern states - ''Culex quinquefasciatus''
* Western states and overlapping areas of distribution of ''Culex pipiens'' and ''Culex quinquefasciatus'' - ''Culex tarsal is''


Some birds behave as '''amplifier hosts'''.  Particularly those of the order ''Passeriformes'', develop high viral loads, that infect mosquitos that feed upod their blood.<ref name=CDC>{{cite web | title = Emerging Infectious Diseases | url = http://wwwnc.cdc.gov/eid/article/9/3/02-0628_article }}</ref>  Humans, on the other hand, behave as '''dead-end hosts''' since they do not develop high-level serum [[viremia]]s to infect mosquitoes.<ref name="pmid20874087">{{cite journal| author=Zou S, Foster GA, Dodd RY, Petersen LR, Stramer SL| title=West Nile fever characteristics among viremic persons identified through blood donor screening. | journal=J Infect Dis | year= 2010 | volume= 202 | issue= 9 | pages= 1354-61 | pmid=20874087 | doi=10.1086/656602 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20874087  }} </ref><ref name="pmid14500806">{{cite journal| author=Pealer LN, Marfin AA, Petersen LR, Lanciotti RS, Page PL, Stramer SL et al.| title=Transmission of West Nile virus through blood transfusion in the United States in 2002. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 13 | pages= 1236-45 | pmid=14500806 | doi=10.1056/NEJMoa030969 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14500806 }} </ref>
==Transmission==
Birds are the main reservoir of West Nile virus (WNV). Transmission of the virus is by a mosquito bite of an infected bird with high-level viremia, such as birds of the family ''Passeriformes''.<ref name=CDC>{{cite web | title = Emerging Infectious Diseases | url = http://wwwnc.cdc.gov/eid/article/9/3/02-0628_article }}</ref>  Thus, transmission is frequently denoted as "bird-mosquito-bird" transmission. Other forms of transmission have been speculated, such as direct bird-to-bird transmission, but further validation is still required.<ref name="pmid12643825">{{cite journal| author=Komar N, Langevin S, Hinten S, Nemeth N, Edwards E, Hettler D et al.| title=Experimental infection of North American birds with the New York 1999 strain of West Nile virus. | journal=Emerg Infect Dis | year= 2003 | volume= 9 | issue= 3 | pages= 311-22 | pmid=12643825 | doi=10.3201/eid0903.020628 | pmc=PMC2958552 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12643825 ; }} </ref> Other species may also be infected, such as horses, cats, and dogs. Humans are considered dead-end hosts because the disease rarely progresses to viremia in humans, making transmission of the virus from a human unlikely except in some reported cases of transmission by blood transfusion, breastfeeding, or organ transplantation.<ref name="pmid12773646">{{cite journal| author=Iwamoto M, Jernigan DB, Guasch A, Trepka MJ, Blackmore CG, Hellinger WC et al.| title=Transmission of West Nile virus from an organ donor to four transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 348 | issue= 22 | pages= 2196-203 | pmid=12773646 | doi=10.1056/NEJMoa022987 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12773646 ; }} </ref><ref name="pmid14500806">{{cite journal| author=Pealer LN, Marfin AA, Petersen LR, Lanciotti RS, Page PL, Stramer SL et al.| title=Transmission of West Nile virus through blood transfusion in the United States in 2002. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 13 | pages= 1236-45 | pmid=14500806 | doi=10.1056/NEJMoa030969 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14500806 ; }} </ref><ref name="pmid12375687">{{cite journal| author=Centers for Disease Control and Prevention (CDC)| title=Possible West Nile virus transmission to an infant through breast-feeding--Michigan, 2002. | journal=MMWR Morb Mortal Wkly Rep | year= 2002 | volume= 51 | issue= 39 | pages= 877-8 | pmid=12375687 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12375687 ; }} </ref>


Transmission of the virus to the humans is highest during the second half of summer.  Higher temperatures are associated with a shorter period of viral incubation,
Mosquitoes responsible for viral transmission belong to different families, varying based on geographical location:<ref name="pmid23860989">{{cite journal| author=Petersen LR, Brault AC, Nasci RS| title=West Nile virus: review of the literature. | journal=JAMA | year= 2013 | volume= 310 | issue= 3 | pages= 308-15 | pmid=23860989 | doi=10.1001/jama.2013.8042 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23860989 ; }} </ref>
*''Culex pipiens'': Northern half and West of USA
*''Culex quinquefasciatus'': Southeast and West of USA
*''Culex tarsalis'': West of USA


==Pathophysiology==
[[image:WNV Mosquito.png|600px|thumb|center|Approximate geographic distribution of the primary WNV vectors, Cx. pipiens, Cx. quinquefasciatus and Cx. tarsalis<SMALL><SMALL>''[http://www.cdc.gov - Center for Disease Control and Prevention(CDC)]''<ref name="CDC">{{Cite web | title = Center for Disease Control and Prevention (CDC) | url =  http://www.cdc.gov}}</ref></SMALL></SMALL>]]
WNV is a member of the family Flaviviridae (genus Flavivirus). Serologically, it is a member of the Japanese encephalitis virus antigenic complex, which includes St. Louis, Japanese, Kunjin, and Murray Valley encephalitis viruses. WNV was first isolated in the WN province of Uganda in 1937. Human and equine outbreaks have been recorded in portions of Africa, southern
Europe, North America, and Asia. Although it is still not known when or how WNV was introduced into North America, international travel of infected persons to New York, importation of infected birds or mosquitoes, or migration of infected birds are all possibilities.
[http://www.cdc.gov/ncidod/dvbid/westnile/resources/wnv-guidelines-aug-2003.pdf]
The virus is transmitted through mosquito vectors, which bite and infect birds. The birds are amplifying hosts, developing sufficient viral levels to transmit the infection to other biting mosquitoes which go on to infect other birds (in the [[Western hemisphere]] the [[American robin]] and the [[American crow]] are the most common carriers) and also humans. The infected mosquito species vary according to geographical area; in the US ''Culex pipiens'' (Eastern US), ''Culex tarsalis'' (Midwest and West), and ''Culex quinquefasciatus'' (Southeast) are the main sources.<ref>Hayes E B, Komar N, Nasci R S, Montgomery S P, Oleary D R, Campbell G L. "Epidemiology and transmission dynamics of West Nile virus disease." ''Emerging Infectious Diseases Journal'' 2005a; 11: 1167-1173</ref>


In mammals the virus does not multiply as readily, and it is believed that mosquitoes biting infected mammals do not further transmit the virus,<ref>Taylor R M, Hurlbut H S, Dressler H R, Spangler E W, Thrasher D. "Isolation of West Nile virus from ''Culex'' mosquitoes." ''Journal of the Egyptian Medical Association'' 1953; 36: 199-208</ref> making mammals so-called dead-end infections.
Other [[transmission]] routes, not involving [[vector]]s, have also been described:<ref name="CampbellMarfin2002">{{cite journal|last1=Campbell|first1=Grant L|last2=Marfin|first2=Anthony A|last3=Lanciotti|first3=Robert S|last4=Gubler|first4=Duane J|title=West Nile virus|journal=The Lancet Infectious Diseases|volume=2|issue=9|year=2002|pages=519–529|issn=14733099|doi=10.1016/S1473-3099(02)00368-7}}</ref>
*[[Blood transfusion]]s<ref name=MMWR>{{cite web | title = Investigations of West Nile Virus Infections in Recipients of Organ Transplantation and Blood Transfusion | url = http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5137a5.htm }}</ref>
*Breast milk<ref name=MMWR>{{cite web | title = Possible West Nile Virus Transmission to an Infant Through Breast-Feeding - Michigan, 2002 | url = http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5139a1.htm }}</ref>
*[[Organ transplant]]s (patients with organ transplants also carry an increased risk of neuroinvasive disease)<ref name="IwamotoJernigan2003">{{cite journal|last1=Iwamoto|first1=Martha|last2=Jernigan|first2=Daniel B.|last3=Guasch|first3=Antonio|last4=Trepka|first4=Mary Jo|last5=Blackmore|first5=Carina G.|last6=Hellinger|first6=Walter C.|last7=Pham|first7=Si M.|last8=Zaki|first8=Sherif|last9=Lanciotti|first9=Robert S.|last10=Lance-Parker|first10=Susan E.|last11=DiazGranados|first11=Carlos A.|last12=Winquist|first12=Andrea G.|last13=Perlino|first13=Carl A.|last14=Wiersma|first14=Steven|last15=Hillyer|first15=Krista L.|last16=Goodman|first16=Jesse L.|last17=Marfin|first17=Anthony A.|last18=Chamberland|first18=Mary E.|last19=Petersen|first19=Lyle R.|title=Transmission of West Nile Virus from an Organ Donor to Four Transplant Recipients|journal=New England Journal of Medicine|volume=348|issue=22|year=2003|pages=2196–2203|issn=0028-4793|doi=10.1056/NEJMoa022987}}</ref>
*Intrauterine [[transmission]]<ref name=MMWR>{{cite web | title = Intrauterine West Nile Virus Infection - New York, 2002 | url = http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5150a3.htm }}</ref>
*Exposure in a laboratory setting<ref name=CDC>{{cite web | title = West Nile Virus Infection | url = http://www.cdc.gov }}</ref>


A 2004 paper in ''Science'' found that ''Culex pipiens'' mosquitoes existed in two populations in [[Europe]], one which bites birds and one which bites humans. In North America 40% of ''Culex pipiens'' were found to be hybrids of the two types which bite both birds and humans, providing a vector for West Nile virus. This is thought to provide an explanation of why the West Nile disease has spread more quickly in North America than Europe.
==Pathogenesis==
Following inoculation, replication of WNV takes place in the Langerhans epidermal dendritic cells, which are antigen-presenting immune cells.<ref name="pmid11564180">{{cite journal| author=Byrne SN, Halliday GM, Johnston LJ, King NJ| title=Interleukin-1beta but not tumor necrosis factor is involved in West Nile virus-induced Langerhans cell migration from the skin in C57BL/6 mice. | journal=J Invest Dermatol | year= 2001 | volume= 117 | issue= 3 | pages= 702-9 | pmid=11564180 | doi=10.1046/j.0022-202x.2001.01454.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11564180 ; }} </ref> These cells then migrate to lymph nodes, resulting in lymph node drainage, followed by viremia and dissemination of the virus into other organs, namely the spleen and the kidneys. Within one week, the virus is successfully cleared from the serum and tissue compartments among immunocompetent individuals. Interferons (IFN) have a crucial role in upregulating genes that carry antiviral functions and in stimulating the maturation of dendritic cells that eventually combine both the innate and the adaptive immune responses.<ref name="pmid15795237">{{cite journal| author=Asselin-Paturel C, Brizard G, Chemin K, Boonstra A, O'Garra A, Vicari A et al.| title=Type I interferon dependence of plasmacytoid dendritic cell activation and migration. | journal=J Exp Med | year= 2005 | volume= 201 | issue= 7 | pages= 1157-67 | pmid=15795237 | doi=10.1084/jem.20041930 | pmc=PMC2213121 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15795237  }} </ref> Viral sensors, such as Toll-like receptor 3, help in activation of transcription factors and IFN-stimulated genes.<ref name="pmid12719735">{{cite journal| author=Barton GM, Medzhitov R| title=Linking Toll-like receptors to IFN-alpha/beta expression. | journal=Nat Immunol | year= 2003 | volume= 4 | issue= 5 | pages= 432-3 | pmid=12719735 | doi=10.1038/ni0503-432 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12719735  }} </ref><ref name="pmid16973548">{{cite journal| author=Keller BC, Fredericksen BL, Samuel MA, Mock RE, Mason PW, Diamond MS et al.| title=Resistance to alpha/beta interferon is a determinant of West Nile virus replication fitness and virulence. | journal=J Virol | year= 2006 | volume= 80 | issue= 19 | pages= 9424-34 | pmid=16973548 | doi=10.1128/JVI.00768-06 | pmc=PMC1617238 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16973548  }} </ref> Additionally, complement activation through classical, lectin, and alternative pathways offers significant immunity against WNV by opsonization, cytolysis, and chemotaxis. Innate immune cells, such as macrophages, along with humoral, primary, and memory adaptive immune cells are also activated during viral infection; these cells also contribute to the clearance of the virus and the prevention of its dissemination to the CNS.<ref name="pmid16973541">{{cite journal| author=Samuel MA, Diamond MS| title=Pathogenesis of West Nile Virus infection: a balance between virulence, innate and adaptive immunity, and viral evasion. | journal=J Virol | year= 2006 | volume= 80 | issue= 19 | pages= 9349-60 | pmid=16973541 | doi=10.1128/JVI.01122-06 | pmc=PMC1617273 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16973541  }} </ref> 


It was initially believed that direct human-to-human transmission was only caused by occupational exposure,<ref>CDC. "Laboratory-acquired West Nile virus infections - United States,2002." ''MMWR'' 2002c; 51: 1133-1135.</ref> or conjunctival exposure to infected blood.<ref>Fonseca K, Prince G D, Bratvold J, Fox J D, Pybus M, Preksaitis J K, Tilley P. "West Nile virus infection and conjunctival exposure." ''Emerging Infectious Diseases Journal'' 3005; 11: 1648-1649.</ref> The US outbreak revealed novel transmission methods, through blood transfusion,<ref>CDC. "Investigation of blood transfusion recipients with West Nile virus infections." ''MMWR'' 2002b; 51: 823.</ref> organ transplant,<ref>CDC. "West Nile virus infection in organ donor and transplant recipients - Georgia and Florida, 2002." ''MMWR'' 2002e; 51: 790.</ref> intrauterine exposure,<ref>CDC. "Intrauterine West Nile virus infection - New York, 2002." ''MMWR'' 2002a; 51: 1135-1136.</ref> and breast feeding.<ref>CDC. "Possible West Nile virus transmission to an infant through breast-feeding - Michigan, 2002." ''MMWR'' 2002d; 51: 877-878.</ref> Since 2003 blood banks in the US routinely screen for the virus amongst their donors.<ref>CDC. "Detection of West Nile virus in blood donations - United States, 2003." ''MMWR'' 2003; 52: 769-772</ref> As a precautionary measure, the UK's [[National Blood Service]] runs a test for this disease in donors who donate within 28 days of a visit to the United States or [[Canada]].
Mice models have demonstrated that persistent infection, including CNS infiltration, is possible, especially in immunosuppressed states. TNF-alpha has been hypothesized to allow viral migration across the blood-brain barrier (BBB) by promoting  the permeability of endothelial cell.<ref name="pmid14662909">{{cite journal| author=Diamond MS, Sitati EM, Friend LD, Higgs S, Shrestha B, Engle M| title=A critical role for induced IgM in the protection against West Nile virus infection. | journal=J Exp Med | year= 2003 | volume= 198 | issue= 12 | pages= 1853-62 | pmid=14662909 | doi=10.1084/jem.20031223 | pmc=PMC2194144 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14662909 ; }} </ref><ref name="pmid16227257">{{cite journal| author=Samuel MA, Diamond MS| title=Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival. | journal=J Virol | year= 2005 | volume= 79 | issue= 21 | pages= 13350-61 | pmid=16227257 | doi=10.1128/JVI.79.21.13350-13361.2005 | pmc=PMC1262587 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16227257 ; }} </ref><ref name="pmid15558055">{{cite journal| author=Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA| title=Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. | journal=Nat Med | year= 2004 | volume= 10 | issue= 12 | pages= 1366-73 | pmid=15558055 | doi=10.1038/nm1140 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15558055 ; }} </ref> Other reports showed that the virus may cross the BBB either by using the olfactory bulb in a "Trojan horse" mechanism to cross to the CNS, or utilizing passive transport mechanisms, or following a retrograde transport mechanism from peripheral neurons.<ref name="pmid15885841">{{cite journal| author=Kramer-Hämmerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R| title=Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. | journal=Virus Res | year= 2005 | volume= 111 | issue= 2 | pages= 194-213 | pmid=15885841 | doi=10.1016/j.virusres.2005.04.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15885841 ; }} </ref><ref name="pmid6300550">{{cite journal| author=Monath TP, Cropp CB, Harrison AK| title=Mode of entry of a neurotropic arbovirus into the central nervous system. Reinvestigation of an old controversy. | journal=Lab Invest | year= 1983 | volume= 48 | issue= 4 | pages= 399-410 | pmid=6300550 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6300550 ; }} </ref><ref name="pmid16310859">{{cite journal| author=Garcia-Tapia D, Loiacono CM, Kleiboeker SB| title=Replication of West Nile virus in equine peripheral blood mononuclear cells. | journal=Vet Immunol Immunopathol | year= 2006 | volume= 110 | issue= 3-4 | pages= 229-44 | pmid=16310859 | doi=10.1016/j.vetimm.2005.10.003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16310859 ; }} </ref>
 
==Tropism==
WNV may be disseminated to include all organ systems. Animal models demonstrated that WNV infection typically first appears in the lymphatic tissue and the spleen before it migrates to other organs, namely the kidneys, lungs, liver, the cardiovascular system, and the nervous system.<ref name="pmid23731695">{{cite journal| author=Gamino V, Höfle U| title=Pathology and tissue tropism of natural West Nile virus infection in birds: a review. | journal=Vet Res | year= 2013 | volume= 44 | issue=  | pages= 39 | pmid=23731695 | doi=10.1186/1297-9716-44-39 | pmc=PMC3686667 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23731695  }} </ref>
In animals, tropism of WNV has been described in the following organs:
*Eyes
*Peripheral and central nervous system
*Heart
*Blood vessels
*Spleen and other lymphoid organs
*Liver
*Kidneys
*Lungs
*GI tract
*Endocrine system, including gonads
*Skeletal muscles
*Skin
*Bone marrow
 
==Genetics==
Genetic factors may be associated with WNV susceptibility. In mice strains, a truncated isoform mutation of the gene encoding OAS1b may lead to susceptibility of infections by WNV and other flaviviruses. Similarly, human subjects with ''CCR5-Δ32'', a mutant allele of the gene encoding chemokine receptor, were more likely to be symptomatic with worse WNV clinical disease. Nonetheless, the true role of genetics in the susceptibility and resistance to WNV is yet to be elucidated.<ref name="pmid16418398">{{cite journal| author=Glass WG, McDermott DH, Lim JK, Lekhong S, Yu SF, Frank WA et al.| title=CCR5 deficiency increases risk of symptomatic West Nile virus infection. | journal=J Exp Med | year= 2006 | volume= 203 | issue= 1 | pages= 35-40 | pmid=16418398 | doi=10.1084/jem.20051970 | pmc=PMC2118086 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16418398 ; }} </ref><ref name="pmid16235172">{{cite journal| author=Yakub I, Lillibridge KM, Moran A, Gonzalez OY, Belmont J, Gibbs RA et al.| title=Single nucleotide polymorphisms in genes for 2'-5'-oligoadenylate synthetase and RNase L inpatients hospitalized with West Nile virus infection. | journal=J Infect Dis | year= 2005 | volume= 192 | issue= 10 | pages= 1741-8 | pmid=16235172 | doi=10.1086/497340 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16235172 ; }} </ref>


==References==
==References==
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[[Category:Disease]]
[[Category:Disease]]
[[Category:Infectious disease]]
 
[[Category:Neurology]]
[[Category:Neurology]]

Latest revision as of 19:28, 18 September 2017


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

Overview

The natural reservoir of West Nile virus (WNV) is birds, particularly species with high-level viremia. In contrast, viremia is relatively rare among infected humans, who are considered dead-end hosts of the virus. WNV is transmitted by bites of various species of mosquitoes. Following inoculation, replication of the virus occurs in the Langerhans epidermal dendritic cell. Among immunocompetent hosts, the replication process is immediately followed by activation of the immune system, including complement pathways, and humoral and adaptive immune responses that act simultaneously to clear the infection. On the other hand, immunocompromised patients may suffer CNS dissemination and fatal outcomes due to the failure to activate proper immunological pathways. Finally, the role of genetics in WNV susceptibility is not fully understood; but mice models and a few human experiments have described genetic mutations that may predispose individuals to worse clinical disease of WNV infections.

West Nile virus life cycle

The West Nile virus has an enzootic life cycle, being primarily transmitted between some species of birds and different species of mosquito vectors.[1]

West Nile virus life cycle- Center for Disease Control and Prevention(CDC)[2]

Transmission

Birds are the main reservoir of West Nile virus (WNV). Transmission of the virus is by a mosquito bite of an infected bird with high-level viremia, such as birds of the family Passeriformes.[2] Thus, transmission is frequently denoted as "bird-mosquito-bird" transmission. Other forms of transmission have been speculated, such as direct bird-to-bird transmission, but further validation is still required.[3] Other species may also be infected, such as horses, cats, and dogs. Humans are considered dead-end hosts because the disease rarely progresses to viremia in humans, making transmission of the virus from a human unlikely except in some reported cases of transmission by blood transfusion, breastfeeding, or organ transplantation.[4][5][6]

Mosquitoes responsible for viral transmission belong to different families, varying based on geographical location:[7]

  • Culex pipiens: Northern half and West of USA
  • Culex quinquefasciatus: Southeast and West of USA
  • Culex tarsalis: West of USA
Approximate geographic distribution of the primary WNV vectors, Cx. pipiens, Cx. quinquefasciatus and Cx. tarsalis- Center for Disease Control and Prevention(CDC)[2]

Other transmission routes, not involving vectors, have also been described:[1]

Pathogenesis

Following inoculation, replication of WNV takes place in the Langerhans epidermal dendritic cells, which are antigen-presenting immune cells.[10] These cells then migrate to lymph nodes, resulting in lymph node drainage, followed by viremia and dissemination of the virus into other organs, namely the spleen and the kidneys. Within one week, the virus is successfully cleared from the serum and tissue compartments among immunocompetent individuals. Interferons (IFN) have a crucial role in upregulating genes that carry antiviral functions and in stimulating the maturation of dendritic cells that eventually combine both the innate and the adaptive immune responses.[11] Viral sensors, such as Toll-like receptor 3, help in activation of transcription factors and IFN-stimulated genes.[12][13] Additionally, complement activation through classical, lectin, and alternative pathways offers significant immunity against WNV by opsonization, cytolysis, and chemotaxis. Innate immune cells, such as macrophages, along with humoral, primary, and memory adaptive immune cells are also activated during viral infection; these cells also contribute to the clearance of the virus and the prevention of its dissemination to the CNS.[14]

Mice models have demonstrated that persistent infection, including CNS infiltration, is possible, especially in immunosuppressed states. TNF-alpha has been hypothesized to allow viral migration across the blood-brain barrier (BBB) by promoting the permeability of endothelial cell.[15][16][17] Other reports showed that the virus may cross the BBB either by using the olfactory bulb in a "Trojan horse" mechanism to cross to the CNS, or utilizing passive transport mechanisms, or following a retrograde transport mechanism from peripheral neurons.[18][19][20]

Tropism

WNV may be disseminated to include all organ systems. Animal models demonstrated that WNV infection typically first appears in the lymphatic tissue and the spleen before it migrates to other organs, namely the kidneys, lungs, liver, the cardiovascular system, and the nervous system.[21] In animals, tropism of WNV has been described in the following organs:

  • Eyes
  • Peripheral and central nervous system
  • Heart
  • Blood vessels
  • Spleen and other lymphoid organs
  • Liver
  • Kidneys
  • Lungs
  • GI tract
  • Endocrine system, including gonads
  • Skeletal muscles
  • Skin
  • Bone marrow

Genetics

Genetic factors may be associated with WNV susceptibility. In mice strains, a truncated isoform mutation of the gene encoding OAS1b may lead to susceptibility of infections by WNV and other flaviviruses. Similarly, human subjects with CCR5-Δ32, a mutant allele of the gene encoding chemokine receptor, were more likely to be symptomatic with worse WNV clinical disease. Nonetheless, the true role of genetics in the susceptibility and resistance to WNV is yet to be elucidated.[22][23]

References

  1. ↑ 1.0 1.1 Campbell, Grant L; Marfin, Anthony A; Lanciotti, Robert S; Gubler, Duane J (2002). "West Nile virus". The Lancet Infectious Diseases. 2 (9): 519–529. doi:10.1016/S1473-3099(02)00368-7. ISSN 1473-3099.
  2. ↑ 2.0 2.1 2.2 2.3 "Center for Disease Control and Prevention (CDC)".
  3. ↑ Komar N, Langevin S, Hinten S, Nemeth N, Edwards E, Hettler D; et al. (2003). ; "Experimental infection of North American birds with the New York 1999 strain of West Nile virus" Check |url= value (help). Emerg Infect Dis. 9 (3): 311–22. doi:10.3201/eid0903.020628. PMC 2958552. PMID 12643825.
  4. ↑ Iwamoto M, Jernigan DB, Guasch A, Trepka MJ, Blackmore CG, Hellinger WC; et al. (2003). ; "Transmission of West Nile virus from an organ donor to four transplant recipients" Check |url= value (help). N Engl J Med. 348 (22): 2196–203. doi:10.1056/NEJMoa022987. PMID 12773646.
  5. ↑ Pealer LN, Marfin AA, Petersen LR, Lanciotti RS, Page PL, Stramer SL; et al. (2003). ; "Transmission of West Nile virus through blood transfusion in the United States in 2002" Check |url= value (help). N Engl J Med. 349 (13): 1236–45. doi:10.1056/NEJMoa030969. PMID 14500806.
  6. ↑ Centers for Disease Control and Prevention (CDC) (2002). ; "Possible West Nile virus transmission to an infant through breast-feeding--Michigan, 2002" Check |url= value (help). MMWR Morb Mortal Wkly Rep. 51 (39): 877–8. PMID 12375687.
  7. ↑ Petersen LR, Brault AC, Nasci RS (2013). ; "West Nile virus: review of the literature" Check |url= value (help). JAMA. 310 (3): 308–15. doi:10.1001/jama.2013.8042. PMID 23860989.
  8. ↑ 8.0 8.1 8.2 "Investigations of West Nile Virus Infections in Recipients of Organ Transplantation and Blood Transfusion".
  9. ↑ Iwamoto, Martha; Jernigan, Daniel B.; Guasch, Antonio; Trepka, Mary Jo; Blackmore, Carina G.; Hellinger, Walter C.; Pham, Si M.; Zaki, Sherif; Lanciotti, Robert S.; Lance-Parker, Susan E.; DiazGranados, Carlos A.; Winquist, Andrea G.; Perlino, Carl A.; Wiersma, Steven; Hillyer, Krista L.; Goodman, Jesse L.; Marfin, Anthony A.; Chamberland, Mary E.; Petersen, Lyle R. (2003). "Transmission of West Nile Virus from an Organ Donor to Four Transplant Recipients". New England Journal of Medicine. 348 (22): 2196–2203. doi:10.1056/NEJMoa022987. ISSN 0028-4793.
  10. ↑ Byrne SN, Halliday GM, Johnston LJ, King NJ (2001). ; "Interleukin-1beta but not tumor necrosis factor is involved in West Nile virus-induced Langerhans cell migration from the skin in C57BL/6 mice" Check |url= value (help). J Invest Dermatol. 117 (3): 702–9. doi:10.1046/j.0022-202x.2001.01454.x. PMID 11564180.
  11. ↑ Asselin-Paturel C, Brizard G, Chemin K, Boonstra A, O'Garra A, Vicari A; et al. (2005). "Type I interferon dependence of plasmacytoid dendritic cell activation and migration". J Exp Med. 201 (7): 1157–67. doi:10.1084/jem.20041930. PMC 2213121. PMID 15795237.
  12. ↑ Barton GM, Medzhitov R (2003). "Linking Toll-like receptors to IFN-alpha/beta expression". Nat Immunol. 4 (5): 432–3. doi:10.1038/ni0503-432. PMID 12719735.
  13. ↑ Keller BC, Fredericksen BL, Samuel MA, Mock RE, Mason PW, Diamond MS; et al. (2006). "Resistance to alpha/beta interferon is a determinant of West Nile virus replication fitness and virulence". J Virol. 80 (19): 9424–34. doi:10.1128/JVI.00768-06. PMC 1617238. PMID 16973548.
  14. ↑ Samuel MA, Diamond MS (2006). "Pathogenesis of West Nile Virus infection: a balance between virulence, innate and adaptive immunity, and viral evasion". J Virol. 80 (19): 9349–60. doi:10.1128/JVI.01122-06. PMC 1617273. PMID 16973541.
  15. ↑ Diamond MS, Sitati EM, Friend LD, Higgs S, Shrestha B, Engle M (2003). ; "A critical role for induced IgM in the protection against West Nile virus infection" Check |url= value (help). J Exp Med. 198 (12): 1853–62. doi:10.1084/jem.20031223. PMC 2194144. PMID 14662909.
  16. ↑ Samuel MA, Diamond MS (2005). ; "Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival" Check |url= value (help). J Virol. 79 (21): 13350–61. doi:10.1128/JVI.79.21.13350-13361.2005. PMC 1262587. PMID 16227257.
  17. ↑ Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA (2004). ; "Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis" Check |url= value (help). Nat Med. 10 (12): 1366–73. doi:10.1038/nm1140. PMID 15558055.
  18. ↑ Kramer-Hämmerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R (2005). ; "Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus" Check |url= value (help). Virus Res. 111 (2): 194–213. doi:10.1016/j.virusres.2005.04.009. PMID 15885841.
  19. ↑ Monath TP, Cropp CB, Harrison AK (1983). ; "Mode of entry of a neurotropic arbovirus into the central nervous system. Reinvestigation of an old controversy" Check |url= value (help). Lab Invest. 48 (4): 399–410. PMID 6300550.
  20. ↑ Garcia-Tapia D, Loiacono CM, Kleiboeker SB (2006). ; "Replication of West Nile virus in equine peripheral blood mononuclear cells" Check |url= value (help). Vet Immunol Immunopathol. 110 (3–4): 229–44. doi:10.1016/j.vetimm.2005.10.003. PMID 16310859.
  21. ↑ Gamino V, Höfle U (2013). "Pathology and tissue tropism of natural West Nile virus infection in birds: a review". Vet Res. 44: 39. doi:10.1186/1297-9716-44-39. PMC 3686667. PMID 23731695.
  22. ↑ Glass WG, McDermott DH, Lim JK, Lekhong S, Yu SF, Frank WA; et al. (2006). ; "CCR5 deficiency increases risk of symptomatic West Nile virus infection" Check |url= value (help). J Exp Med. 203 (1): 35–40. doi:10.1084/jem.20051970. PMC 2118086. PMID 16418398.
  23. ↑ Yakub I, Lillibridge KM, Moran A, Gonzalez OY, Belmont J, Gibbs RA; et al. (2005). ; "Single nucleotide polymorphisms in genes for 2'-5'-oligoadenylate synthetase and RNase L inpatients hospitalized with West Nile virus infection" Check |url= value (help). J Infect Dis. 192 (10): 1741–8. doi:10.1086/497340. PMID 16235172.


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