A neuron-specific antiviral mechanism prevents lethal flaviviral infection of mosquitoes.
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.
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, People's Republic of China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China.
Xiaoping
X
Xiao
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, People's Republic of China; School of Life Science, Tsinghua University, Beijing, People's Republic of China.
Rudian
R
Zhang
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, People's Republic of China.
Xiaojing
X
Pang
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China; State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Viral Disease Control and Prevention, Beijing, People's Republic of China.
Guodong
G
Liang
Department of Microbiology and Immunology, School of Medicine, New York Medical College, Valhalla, New York, United States of America.
Penghua
P
Wang
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, People's Republic of China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China.
Gong
G
Cheng
D000330:Aedes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D003716:Dengue Virus / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D004664:Encephalitis Virus, Japanese / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D005260:Female; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D019476:Insect Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D010802:Phylogeny; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects
D000998:Antiviral Agents; D029721:Drosophila Proteins; D019476:Insect Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins; C098696:hig protein, Drosophila