Prior Exposure to Uninfected Mosquitoes Enhances Mortality in West Nile Virus

[Sally Furniss]

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


Bradley S. Schneider¹^,³, Charles E. McGee¹

, Jeffrey M. Jordan¹, Heather L. Stevenson¹, Lynn Soong¹^,², Stephen Higgs¹^*
1 Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America, 2 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America, 3 Pasteur Institute, Paris, France
Abstract

Background

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. 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 Findings

Here 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.
Significance

This 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.



http://www.plosone.org/article/fetchArticle.action?articleURI=info:doi/10.1371/journal.pone.0001171

 

[AlaskaDenise]

Re: Prior Exposure to Uninfected Mosquitoes Enhances Mortality in West Nile Virus

The implications for all viral diseases is interesting....

Subsequent experiments investigated the mechanism of this divergence in disease severity. The memory response to mosquito proteins could skew the immune response in a manner that compromises early anti-viral defenses. The microenvironment at the site of viral invasion and initial replication, including cytokines and immune cells present can influence the early orchestration of the response and priming of T cells. Previous research related to mosquito allergy demonstrated a T<SUB>H</SUB>1 to T<SUB>H</SUB>2 shift following sensitization to Ae. aegypti [15]. To evaluate whether cytokine expression differed between groups, total RNA was isolated from inoculation site and draining LN for quantifying the relative levels of IL-2, IL-4, IL-10, IL-12p40, IFN-β, and IFN-γ via real-time RT-PCR [9].

In three separate experiments, IL-10 expression was consistently elevated in the dermis and draining LNs of sensitized mice as compared to na?ve mice at 36 h post-infection (p = 0.04)(Fig. 1B). This immuno-regulatory cytokine is multifunctional. In relation to viral infections, IL-10 may create favorable conditions for viral replication by disarming the innate and adaptive responses. In human monocytes, IL-10 and IFN-γ antagonize the function of each other [18]. IL-10 also down regulates MHC class II antigen expression by monocytes and inhibits antigen presentation by several types of antigen-presenting cells (APC), including epidermal LCs [19], [20]. The presence of viruses whose genomes code for IL-10 homologs, demonstrate that there is an evolutionary advantage to enhanced IL-10 levels for an invading virus [21], [22]. Studies with peripheral blood leukocytes found that during the early phase of infection with dengue virus, increased IL-10 production induces lasting T cell inactivation and decreases the control of virus infection [23].

Consequently, the interaction of immunosuppressive IL-10-producing cells with T cells early during WNV infection may result in the loss of T-cell responsiveness and facilitate an enhancement of viral replication and a blunted adaptive immune response. Thus, notwithstanding further effects of prior exposure to mosquitoes, heightened IL-10 production associated with an anti-mosquito immune response may account for the altered course of infection.