Prior Exposure to Uninfected Mosquitoes Enhances Mortality in Naturally-Transmitted West Nile Virus Infection

Bradley S Schneider,Lynn Soong,Jeffrey M Jordan,Charles E Mcgee,Heather L Stevenson,Stephen Higgs,Matthew Baylis

doi:10.1371/journal.pone.0001171

Bradley S Schneider, Lynn Soong + Show 5 more

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https://doi.org/10.1371/journal.pone.0001171

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Abstract

BackgroundThe global emergence of West Nile virus (WNV) has highlighted the importance of mosquito-borne viruses. These are inoculated in vector saliva into the vertebrate skin and circulatory system. Arthropod-borne (arbo)viruses such as WNV are transmitted to vertebrates as an infectious mosquito probes the skin for blood, depositing the virus and saliva into the skin and circulation. Growing evidence has demonstrated that arthropod, and recently mosquito, saliva can have a profound effect on pathogen transmission efficiency, pathogenesis, and disease course. A potentially important aspect of natural infections that has been ignored is that in nature vertebrates are typically exposed to the feeding of uninfected mosquitoes prior to the mosquito that transmits WNV. The possibility that pre-exposure to mosquito saliva might modulate WNV infection was explored.Principal FindingsHere we report that sensitization to mosquito saliva exacerbates viral infection. Prior exposure of mice to mosquito feeding resulted in increased mortality following WNV infection. This aggravated disease course was associated with enhanced early viral replication, increased interleukin-10 expression, and elevated influx of WNV-susceptible cell types to the inoculation site. This exacerbated disease course was mimicked by passive transfer of mosquito-sensitized serum.SignificanceThis is the first report that sensitization to arthropod saliva can exacerbate arthropod-borne infection, contrary to previous studies with parasite and bacteria infections. This research suggests that in addition to the seroreactivity of the host to virus, it is important to take into account the immune response to vector feeding.

Highlights

West Nile virus (WNV) is a positive sense, single-stranded RNA virus that emerged globally following the appearance of a more neurotropic subtype [1]
To evaluate whether cytokine expression differed between groups, total RNA was isolated from inoculation site and draining lymph nodes (LN) for quantifying the relative levels of IL-2, IL-4, IL-10, IL-12p40, IFN-b, and IFN-c via real-time RT-PCR [9]
Mice previouslyexposed to mosquito feeding develop significantly higher mortality associated with elevation of inflammation, antigen-presenting cells (APC) recruitment, IL-10 expression in the inoculation site and draining LNs, and LN hyperplasia concurrent with a decrease in lymphocytes of the CD4+ subtype

Summary

Introduction

West Nile virus (WNV) is a positive sense, single-stranded RNA virus (family Flaviviridae) that emerged globally following the appearance of a more neurotropic subtype [1]. WNV has limited replication in the skin; and within 24 h of deposition, infected dendritic cells (DCs), Langerhan cells (LCs), migrate from the epidermis to local lymph nodes (LN) [13]. The global emergence of West Nile virus (WNV) has highlighted the importance of mosquito-borne viruses These are inoculated in vector saliva into the vertebrate skin and circulatory system. Prior exposure of mice to mosquito feeding resulted in increased mortality following WNV infection This aggravated disease course was associated with enhanced early viral replication, increased interleukin-10 expression, and elevated influx of WNV-susceptible cell types to the inoculation site. This exacerbated disease course was mimicked by passive transfer of mosquito-sensitized serum. This research suggests that in addition to the seroreactivity of the host to virus, it is important to take into account the immune response to vector feeding

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