Abstract
West Nile Virus (WNV) is a flavivirus involved in many human infections worldwide. This arthropod-borne virus is directly co-inoculated with mosquito saliva through the epidermis and the dermis during blood meal. WNV starts replicating in the skin before migrating to the draining lymph node, leading to widespread viremia and in some cases to neurological symptoms. Skin is a complex organ composed of different cell types that together perform essential functions such as pathogen sensing, barrier maintenance and immunity. Keratinocytes, which represent 90% of the cells of the epidermis, are the organism's first line of defense, initiating innate immune response by recognizing pathogens through their pattern recognition receptors. Although WNV was previously known to replicate in human primary keratinocytes, the induced inflammatory response remains unknown. The aim of this study was first to characterize the inflammatory response of human primary keratinocytes to WNV infection and then, to assess the potential role of co-inoculated mosquito saliva on the keratinocyte immune response and viral replication. A type I and III interferon inflammatory response associated with an increase of IRF7 but not IRF3 mRNA expression, and dependent on infectious dose, was observed during keratinocyte infection with WNV. Expression of several interferon-stimulated gene mRNA was also increased at 24 h post-infection (p.i.); they included CXCL10 and interferon-induced proteins with tetratricopeptide repeats (IFIT)-2 sustained up until 48 h p.i. Moreover, WNV infection of keratinocyte resulted in a significant increase of pro-inflammatory cytokines (TNFα, IL-6) and various chemokines (CXCL1, CXCL2, CXCL8 and CCL20) expression. The addition of Aedes aegypti or Culex quinquefasciatus mosquito saliva, two vectors of WNV infection, to infected keratinocytes led to a decrease of inflammatory response at 24 h p.i. However, only Ae. Aegypti saliva adjunction induced modulation of viral replication. In conclusion, this work describes for the first time the inflammatory response of human primary keratinocytes to WNV infection and its modulation in presence of vector mosquito saliva. The effects of mosquito saliva assessed in this work could be involved in the early steps of WNV replication in skin promoting viral spread through the body.
Highlights
Since its discovery in 1937 from a febrile woman in Uganda, West Nile virus (WNV) has been involved in mild febrile disease outbreaks in Africa, Asia and Europe (Lim et al, 2011)
Keratinocytes were seeded at a density of 107 cells in 75-cm2 tissue culture flask in Keratinocyte-Serum Free Medium (K-SFM) supplemented with bovine pituitary extract (25 μg/mL) and recombinant epidermal growth factor (EGF) (0.25 ng/mL; all were purchased from Invitrogen, Life Technologies)
IFIT2 mRNA expression was Primary Human Keratinocytes Are Permissive to West Nile Virus (WNV) Infection
Summary
Since its discovery in 1937 from a febrile woman in Uganda, West Nile virus (WNV) has been involved in mild febrile disease outbreaks in Africa, Asia and Europe (Lim et al, 2011). It is endemic on the North American continent after its introduction in 1999 (Lanciotti et al, 1999) and propagating southward. WNV primary hosts are birds while mammals, humans and horses, represent accidental and deadend hosts infected through the inoculation by infected female mosquitoes (Kramer et al, 2008). Culex mosquitoes participate in an enzootic cycle between birds and represent a “bridge” vectors between the avian and mammalian hosts (Turell et al, 2005) because of their opportunistic feeding behavior
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