A Neuron-Specific Antiviral Mechanism Prevents Lethal Flaviviral Infection of Mosquitoes

Abstract

Mosquitoes are natural vectors for many etiologic agents of human viral diseases. Mosquito-borne flaviviruses can persistently infect the mosquito central nervous system without causing dramatic pathology or influencing the mosquito behavior and lifespan. The mechanism by which the mosquito nervous system resists flaviviral infection is still largely unknown. Here we report that an Aedes aegypti homologue of the neural factor Hikaru genki (AaHig) efficiently restricts flavivirus infection of the central nervous system. AaHig was predominantly expressed in the mosquito nervous system and localized to the plasma membrane of neural cells. Functional blockade of AaHig enhanced Dengue virus (DENV) and Japanese encephalitis virus (JEV), but not Sindbis virus (SINV), replication in mosquito heads and consequently caused neural apoptosis and a dramatic reduction in the mosquito lifespan. Consistently, delivery of recombinant AaHig to mosquitoes reduced viral infection. Furthermore, the membrane-localized AaHig directly interfaced with a highly conserved motif in the surface envelope proteins of DENV and JEV, and consequently interrupted endocytic viral entry into mosquito cells. Loss of either plasma membrane targeting or virion-binding ability rendered AaHig nonfunctional. Interestingly, Culex pipien pallens Hig also demonstrated a prominent anti-flavivirus activity, suggesting a functionally conserved function for Hig. Our results demonstrate that an evolutionarily conserved antiviral mechanism prevents lethal flaviviral infection of the central nervous system in mosquitoes, and thus may facilitate flaviviral transmission in nature.

Mosquito Defense Strategies against Viral Infection

“…Then, the infected mosquitoes are ready to transmit the virus to other hosts through bites [7–9]. In contrast to the severe diseases observed in vertebrates, persistent viral replication in mosquitoes neither results in dramatic pathological sequelae nor influences mosquito behavior or its lifespan [10]. The infection in mosquitoes is usually associated with few fitness costs, thereby allowing the mosquitoes to transmit the virus efficiently [11].…”

“…As natural vectors, mosquitoes are susceptible to many arboviruses. The heads of mosquitoes (the location of the central neural system) can be persistently infected by arboviruses throughout the mosquito’s lifespan [8,10]. However, viral propagation does not dramatically influence the vectorial capacity in mosquitoes by affecting their behavior or lifespan; thus, infection does not apparently result in severe pathological sequelae in the mosquito neural system [10,89,90].…”

“…The heads of mosquitoes (the location of the central neural system) can be persistently infected by arboviruses throughout the mosquito’s lifespan [8,10]. However, viral propagation does not dramatically influence the vectorial capacity in mosquitoes by affecting their behavior or lifespan; thus, infection does not apparently result in severe pathological sequelae in the mosquito neural system [10,89,90]. A recent study reported a neuron-specific factor in A. aegypti and C. pipien pallens that encoded multiple mammalian complement-related domains and specifically controlled DENV and JEV replication in the nervous system by interfering with viral entry; its activity prevented lethal flaviviral infection of mosquitoes (Figure 1E) [10].…”

“…However, viral propagation does not dramatically influence the vectorial capacity in mosquitoes by affecting their behavior or lifespan; thus, infection does not apparently result in severe pathological sequelae in the mosquito neural system [10,89,90]. A recent study reported a neuron-specific factor in A. aegypti and C. pipien pallens that encoded multiple mammalian complement-related domains and specifically controlled DENV and JEV replication in the nervous system by interfering with viral entry; its activity prevented lethal flaviviral infection of mosquitoes (Figure 1E) [10]. Indeed, a comparative genomic analysis suggested that while most human complement components had no mosquito orthologues, the complement-related modules were largely evolutionarily conserved between mosquitoes and humans.…”

“…A CCP-containing protein in A. aegypti (designated Aedes aegypti Hikaru genki or AaHig ) are specifically expressed in the nervous system and localize to the surface of mosquito neural cells to efficiently capture DENV and JEV virions via their CCP modules, thereby directly interrupting viral entry into mosquito cells and limiting viral propagation in the mosquito nervous system. Functional blockade of AaHig in flavivirus-infected mosquitoes results in apoptotic damage to mosquito neural cells and a reduction of their lifespan [10]. This antiviral strategy does not alter viral replication in non-neural tissues such as the salivary glands but may facilitate viral transmission productivity in nature by extending the life span of infected mosquitoes.…”