Host Immune Response to Mosquito-Transmitted Chikungunya Virus Differs from That Elicited by Needle Inoculated Virus

et al. (2010) Host Immune Response to Mosquito-Transmitted Chikungunya Virus Differs from That Elicited by Needle Inoculated Virus. PLoS ONE 5(8): e12137. doi:10.1371/journal.pone.0012137 Host Immune Response to Mosquito-Transmitted Chikungunya Virus Differs from That Elicited by Needle Inoculated Virus Saravanan Thangamani 0 Stephen Higgs 0 Sarah Ziegler 0 Dana Vanlandingham 0 Robert Tesh 0 Stephen Wikel 0 Bradley S. Schneider, Global Viral Forecasting Initiative, United States of America 0 1 Department of Pathology, University of Texas Medical Branch , Galveston, Texas , United States of America, 2 Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch , Galveston, Texas , United States of America, 3 Sealy Center for Vaccine Development, University of Texas Medical Branch , Galveston, Texas , United States of America Background: Mosquito-borne diseases are a worldwide public health threat. Mosquitoes transmit viruses or parasites during feeding, along with salivary proteins that modulate host responses to facilitate both blood feeding and pathogen transmission. Understanding these earliest events in mosquito transmission of arboviruses by mosquitoes is essential for development and assessment of rational vaccine and treatment strategies. In this report, we compared host immune responses to chikungunya virus (CHIKV) transmission by (1) mosquito bite, or (2) by needle inoculation. Methods and Findings: Differential cytokine expression was measured using quantitative real-time RT-PCR, at sites of uninfected mosquito bites, CHIKV-infected mosquito bites, and needle-inoculated CHIKV. Both uninfected and CHIKV infected mosquitoes polarized host cytokine response to a TH2 profile. Compared to uninfected mosquito bites, expression of IL-4 induced by CHIKV-infected mosquitoes were 150 fold and 527.1 fold higher at 3 hours post feeding (hpf) and 6 hpf, respectively. A significant suppression of TH1 cytokines and TLR-3 was also observed. These significant differences may result from variation in the composition of uninfected and CHIKV-infected mosquito saliva. Needle injected CHIKV induced a robust interferon-c, no detectable IL-4, and a significant up-regulation of TLR-3. Conclusions: This report describes the first analysis of cutaneous cytokines in mice bitten by CHIKV-infected mosquitoes. Our data demonstrate contrasting immune activation in the response to CHIKV infection by mosquito bite or needle inoculation. The significant role of mosquito saliva in these earliest events of CHIKV transmission and infection are highlighted. - Funding: This study was supported by United States Army Medical Research and Materiel Command Award 0310075 and National Institutes of Health (NIH) Grant AI062735 to SW. This study was also supported in part by NIH contract N01-AI25489 and N01-AI30027 to RT, and NIH grant AI R21 AI073389 to SH. SZ is funded by the Sealy Center for Vaccine Development, UTMB, Galveston. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Mosquitoes are a significant public health problem because of their ability to transmit a variety of arboviruses and also the causative agents of malaria and filariasis to susceptible humans (www.who.int/ tdr/diseases). Mosquito-borne diseases continue to emerge and reemerge [1,2] as demonstrated by the recent chikungunya epidemics on Indian Ocean islands and in India since 2005. Chikungunya virus (CHIKV) is an Alphavirus belonging to family Togaviridae, which is transmitted predominantly by Aedes aegypti and Ae. albopticus (www. cdc.gov/ncidod/dvbid/Chikungunya). Both mosquito species occur over vast regions of the world, including the United States, southern Europe, and tropical regions of South America, Africa, and Asia posing the very real threat that new transmission cycles could be established in these regions [3]. Since 2005, CHIK fever has been identified in an unprecedented number of travelers returning home from epidemic areas to Europe, United States, Australia, and Japan [3,4,5,6,7]. Imported CHIKV infection in returned travelers paralleled the spread of the explosive outbreaks in the Indian Ocean islands and India. In 2006, CHIKV infections were detected in Singapore among travelers returning home after visiting India and Malaysia. Those sporadic imported cases preceded the 2008 chikungunya outbreaks in Singapore, demonstrating the potential for introducing this emerging viral infection into new areas and establishing a transmission cycle with competent local vector mosquito species [8]. Thus, there is a clear risk of importing CHIKV into new ecological niches through infected travelers returning from popular tourist destinations with CHIKV epidemics. Human infections with CHIKV occur during blood feeding by infected Aedes mosquitoes. Mosquito saliva contains a re (...truncated)