Identification of Culex tarsalis D7 salivary protein and role of salivary protein vaccine on subsequent West Nile virus infection
Date
2010
Authors
Reagan, Krystle Lynn, author
Blair, Carol D., advisor
Olson, Kenneth Edward, committee member
Foy, Brian D., committee member
Chen, Chaoping, committee member
Wang, Tian, committee member
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Abstract
Mosquito salivary proteins (MSPs) modulate the host immune response, leading to enhancement of arboviral infections. Identification of protein factors in saliva responsible for immunomodulation should lead to new strategies to prevent and protect against arboviral infection. D7 salivary proteins are among the most abundant in mosquito saliva, and they function as both vasodilators and suppressors of local inflammation. Here we identify D7 salivary proteins in Culex tarsalis, an important disease vector in the western United States. Recombinant D7 proteins were used to analyze the systemic and local immunomodulatory properties of the host. In this project, we immunized mice with recombinant D7 and tested for protection against subsequent challenge with West Nile virus (WNV) (NY99) delivered by mosquito bite. The vaccine was able to elicit a specific immune response. However, it enhanced WNV infection in the mouse model. We suggest that WNV enhancement is due to three factors. First, vaccinated mice had significant cellular infiltrates at the mosquito bite site, which included WNV permissive monocytes and dendritic cells. Increases in these cell populations at the mosquito bite site leads to an increase in initial viral infection and dissemination. Others have shown that higher peripheral viral levels lead to a worse disease outcome from infection. Secondly, mortality curves in infected mice receiving passive transfer of serum containing antibodies from vaccinated mice mimicked those from vaccinated animals. Antibody neutralization of mosquito salivary proteins that are critical in completing a successful blood meal may lead to increased probing time by the mosquito. Increased probing by the mosquito results in an increase in amount of saliva being deposited, therefore an increase in initial viral dose. Lastly, the cytokine profile observed in vaccinated mice showed an increase in the Th2 cytokine IL-4 and regulatory cytokine IL-10 and a decrease in Th1 cytokines such as IL-12p70 and IFNγ. A protective immune response to WNV includes high levels of Th1 cytokines. Production of IL-4 by mice that received the rD7 vaccine directly inhibits the Th1 cytokines necessary for protection. This work has increased our understanding of the complex nature of immunity to MSPs. Vector saliva vaccines have been successful in protecting against other blood feeding arthropods transmitted diseases. Nevertheless, differences in vector and pathogen physiology may preclude this approach from being successful for mosquito virus systems.
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Subject
West Nile virus
Culex tarsalis
Recombinant proteins
Mosquitoes as carriers of disease