West nile virus pathophysiology

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Pathogenesis

Following inoculation, replication of WNV takes place in Langerhans epidermal dendritic cells, which are antigen-presenting immune cells.[1] 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 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.[2] Viral sensors, such as Toll-like receptor 3, help in activation of transcription factors and IFN-stimulated genes.[3][4] Similarly, complement activation through classical, lectin, and alternative pathways offers significant immunity against WNV by opsonization, cytolysis, and chemotaxis. Finally, 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.[5]

Mice models have demonstrated that persistent infection, including CNS infiltration, is possible, especially in immunosuppressed states with deficient immunity. TNF-alpha has been hypothesized to allow viral crossing of the blood-brain barrier (BBB) by promoting endothelial cell permeability.[6][7][8] 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 follow a retrograde transport mechanism from peripheral neurons.[9][10][11]

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 found to be more likely to be symptomatic with worse WNV symptoms. Nonetheless, the true role of genetics in the susceptibility and resistance to WNV is yet to be elucidated.[12][13]

  1. ↑ 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". J Invest Dermatol. 117 (3): 702–9. doi:10.1046/j.0022-202x.2001.01454.x. PMID 11564180.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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". J Exp Med. 198 (12): 1853–62. doi:10.1084/jem.20031223. PMC 2194144. PMID 14662909.
  7. ↑ Samuel MA, Diamond MS (2005). "Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival". J Virol. 79 (21): 13350–61. doi:10.1128/JVI.79.21.13350-13361.2005. PMC 1262587. PMID 16227257.
  8. ↑ 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". Nat Med. 10 (12): 1366–73. doi:10.1038/nm1140. PMID 15558055.
  9. ↑ 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". Virus Res. 111 (2): 194–213. doi:10.1016/j.virusres.2005.04.009. PMID 15885841.
  10. ↑ Monath TP, Cropp CB, Harrison AK (1983). "Mode of entry of a neurotropic arbovirus into the central nervous system. Reinvestigation of an old controversy". Lab Invest. 48 (4): 399–410. PMID 6300550.
  11. ↑ Garcia-Tapia D, Loiacono CM, Kleiboeker SB (2006). "Replication of West Nile virus in equine peripheral blood mononuclear cells". Vet Immunol Immunopathol. 110 (3–4): 229–44. doi:10.1016/j.vetimm.2005.10.003. PMID 16310859.
  12. ↑ 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". J Exp Med. 203 (1): 35–40. doi:10.1084/jem.20051970. PMC 2118086. PMID 16418398.
  13. ↑ 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". J Infect Dis. 192 (10): 1741–8. doi:10.1086/497340. PMID 16235172.
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