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Mosquito-borne Zika virus (ZIKV) can cause congenital microcephaly and Guillain-Barré syndrome, among other symptoms. Specific treatments and vaccines for ZIKV are not currently available. To further understand the host factors that support ZIKV replication, we used mass spectrometry to characterize mammalian proteins that associate with the ZIKV NS1 protein and identified the TRiC/CCT complex as an interacting partner. Furthermore, the suppression of CCT2, one of the critical components of the TRiC/CCT complex, inhibited ZIKV replication in both mammalian cells and mosquitoes. These results highlight an important role for the TRiC/CCT complex in ZIKV infection, suggesting that the TRiC/CCT complex may be a promising therapeutic target.

A recent epidemic of Zika virus in the Americas, affecting well over a million people, caused substantial mortality and morbidity, including Guillain-Barre syndrome, microcephaly and other fetal developmental defects 1,2 . Preventive and therapeutic measures that specifically target the virus are not readily available. The transmission of Zika virus is predominantly mosquito-borne, and Aedes aegypti mosquitoes serve as a key vector for Zika virus 3 . Here, to identify salivary factors that modulate mosquito-borne Zika virus infection, we focused on antigenic proteins in mice that were repeatedly bitten by mosquitoes and developed antibodies against salivary proteins. Using a yeast surface display screen, we identified five antigenic A. aegypti salivary proteins in mice. Antiserum against one of these five proteins-A. aegypti bacteria-responsive protein 1 (AgBR1)-suppressed early inflammatory responses in the skin of mice bitten by Zika-virus-infected mosquitoes. AgBR1 antiserum also partially protected mice from lethal mosquito-borne-but not needle-injected-Zika virus infection. These data suggest that AgBR1 is a target for the prevention of mosquito-transmitted Zika virus infection.

Few animal models of Zika virus (ZIKV) infection have incorporated arthropod-borne transmission. Here, we establish an Aedes aegypti mosquito model of ZIKV infection of mice, and demonstrate altered vector competency among three strains, (Orlando, ORL, Ho Chi Minh, HCM, and Patilas, PAT). All strains acquired ZIKV in their midguts after a blood meal from infected mice, but ZIKV transmission only occurred in mice fed upon by HCM, and to a lesser extent PAT, but not ORL, mosquitoes. This defect in transmission from ORL or PAT mosquitoes was overcome by intrathoracic injection of ZIKV into mosquito. Genetic analysis revealed significant diversity among these strains, suggesting a genetic basis for differences in ability for mosquito strains to transmit ZIKV. The intrathoracic injection mosquito-mouse transmission model is critical to understanding the influence of mosquitoes on ZIKV transmission, infectivity and pathogenesis in the vertebrate host, and represents a natural transmission route for testing vaccines and therapeutics.

Saliva from the mosquito vector of flaviviruses is capable of changing the local immune environment, leading to an increase of flavivirus-susceptible cells at the infected bite site. Additionally, an antibody response towards specific salivary gland (SG) components changes the pathogenesis of flavivirus in human populations. To investigate if antigenic SG proteins are capable of enhancing Zika virus (ZIKV) infection, a re-emerging flavivirus primarily transmitted by the Aedes aegypti mosquito, we screened for antigenic SG proteins using a yeast display library, and demonstrate a previously undescribed SG protein, we term neutrophil stimulating factor 1 (NeSt1), activates primary mouse neutrophils ex vivo. Passive immunization against NeSt1 decreases pro-IL-1β and CXCL2 expression, prevents macrophages from infiltrating into the bite site, protects susceptible IFNAR-/-IFNGR-/- (AG129) mice from early ZIKV replication, and ameliorates viral-induced pathogenesis. These findings indicate that NeSt1 stimulates neutrophils at the mosquito bite site to change the immune microenviroment, allowing higher early viral replication and enhancing ZIKV pathogenesis. (156 Words) [ABSTRACT FROM AUTHOR]