SummaryZika virus (ZIKV) remained obscure until the recent explosive outbreaks in French Polynesia (2013-2014) and South America (2015-2016). Phylogenetic studies reveal that ZIKV has evolved into African and Asian lineages. The Asian lineage of ZIKV is responsible for the recent epidemics in the Americas. However, the underlying mechanisms through which ZIKV rapidly and explosively spread from Asia to the Americas are limited. We have recently shown that nonstructural protein 1 (NS1) facilitates flavivirus acquisition by mosquitoes from an infected mammalian host and subsequently enhances viral prevalence in mosquitoes. Here, we report that the antigenemia of NS1 determines ZIKV infectivity in its mosquito vector Aedes aegypti, which acquires ZIKV via a blood meal. Clinical isolates from the most recent outbreak in the Americas were much more infectious in mosquitoes than the FSS13025 strain, which was isolated in Cambodia in 2010. Further analyses showed that these epidemic strains have more robust NS1 antigenemia than the FSS13025 strain because of an alanine-to-valine amino acid substitution at the 188th residue in NS1. ZIKV infectivity was enhanced by this residue substitution in the ZIKV FSS13025 strain in mosquitoes that acquired ZIKV from a viremic Type I and II interferon receptor-deficient (ifnagr-/-) C57BL/6 (AG6) mouse. Our results reveal that ZIKV evolved to acquire a spontaneous mutation in its NS1 protein, resulting in increased antigenemia of the protein. Enhancement of NS1 antigenemia in infected hosts promotes ZIKV infectivity and prevalence in mosquitoes, which potentially facilitates transmission during the recent ZIKV epidemics.
SummaryThe arbovirus life cycle involves viral transfer between a vertebrate host and an arthropod vector, and acquisition of virus from an infected mammalian host by a vector is an essential step in this process. Here, we report that flavivirus nonstructural protein-1 (NS1), which is abundantly secreted into the serum of an infected host, plays a critical role in flavivirus acquisition by mosquitoes. The presence of dengue virus (DENV) and Japanese encephalitis virus (JEV) NS1s in the blood of infected interferon alpha and gamma receptor-deficient mice (AG6) facilitated virus acquisition by their native mosquito vectors because the protein enabled the virus to overcome the immune barrier of the mosquito midgut. Active immunization of AG6 mice with a modified DENV NS1 reduced DENV acquisition by mosquitoes and protected mice against a lethal DENV challenge, suggesting that immunization with NS1 could reduce the number of virus-carrying mosquitoes as well as the incidence of flaviviral diseases. Our study demonstrates that flaviviruses utilize NS1 proteins produced during their vertebrate phases to enhance their acquisition by vectors, which might be a result of flavivirus evolution to adapt to multiple host environments.
Graphical Abstract Highlights d The gut commensal Serratia marcescens promotes mosquito permissiveness to arboviruses d S. marcescens facilitates arboviral infection via a secreted protein named SmEnhancin d SmEnhancin digests gut membrane-bound mucins to enhance viral dissemination in mosquitoes d S. marcescens enhances the susceptibility of field mosquitoes to dengue virus In Brief Wu et al. identified Serratia marcescens as a mosquito gut commensal bacterium critical for efficient arboviral acquisition. S. marcescens facilitates arboviral infection through secretion of a protein named SmEnhancin. Colonization of S. marcescens in field-derived Aedes mosquitoes enhances vector competence. Gut residence of S. marcescens correlates with regionspecific dengue prevalence.
Transmission from an infected mosquito to a host is an essential process in the life cycle of mosquito-borne flaviviruses. Numerous studies have demonstrated that mosquito saliva facilitates viral transmission. Here we find that a saliva-specific protein, named Aedes aegypti venom allergen-1 (AaVA-1), promotes dengue and Zika virus transmission by activating autophagy in host immune cells of the monocyte lineage. The AG6 mice (ifnar1–/–ifngr1–/–) bitten by the virus-infected AaVA-1-deficient mosquitoes present a lower viremia and prolonged survival. AaVA-1 intracellularly interacts with a dominant negative binder of Beclin-1, known as leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), and releases Beclin-1 from LRPPRC-mediated sequestration, thereby enabling the initialization of downstream autophagic signaling. A deficiency in Beclin-1 reduces viral infection in mice and abolishes AaVA-1-mediated enhancement of ZIKV transmission by mosquitoes. Our study provides a mechanistic insight into saliva-aided viral transmission and could offer a potential prophylactic target for reducing flavivirus transmission.
Mosquito‐borne viruses (MBVs) are a large class of viruses transmitted mainly through mosquito bites, including dengue virus, Zika virus, Japanese encephalitis virus, West Nile virus, and chikungunya virus, which pose a major threat to the health of people around the world. With global warming and extended human activities, the incidence of many MBVs has increased significantly. Mosquito saliva contains a variety of bioactive protein components. These not only enable blood feeding but also play a crucial role in regulating local infection at the bite site and the remote dissemination of MBVs as well as in remodeling the innate and adaptive immune responses of host vertebrates. Here, we review the physiological functions of mosquito salivary proteins (MSPs) in detail, the influence and the underlying mechanism of MSPs on the transmission of MBVs, and the current progress and issues that urgently need to be addressed in the research and development of MSP‐based MBV transmission blocking vaccines.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.