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Reliable, easy-to-read patient information on common medical conditions β€” written in plain language, free of jargon, and grounded in current evidence. Browse the most frequent diagnoses, understand what they mean for everyday life, and learn which steps and questions help you have a focused conversation with your doctor.

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West nile virus infection pathophysiology

Introduction

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 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

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

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

[[

image:WNV Mosquito.png|600px|thumb|center|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

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

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

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-Ξ”32, 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

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. ISSNΒ 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. PMCΒ 2958552. PMIDΒ 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. PMIDΒ 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. PMIDΒ 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. PMIDΒ 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. PMIDΒ 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. ISSNΒ 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. PMIDΒ 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. PMCΒ 2213121. PMIDΒ 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. PMIDΒ 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. PMCΒ 1617238. PMIDΒ 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. PMCΒ 1617273. PMIDΒ 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. PMCΒ 2194144. PMIDΒ 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. PMCΒ 1262587. PMIDΒ 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. PMIDΒ 15558055.
  18. ↑ Kramer-HΓ€mmerle 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. PMIDΒ 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. PMIDΒ 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. PMIDΒ 16310859.
  21. ↑ Gamino V, HΓΆfle 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. PMCΒ 3686667. PMIDΒ 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. PMCΒ 2118086. PMIDΒ 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. PMIDΒ 16235172.

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