title: Mosquito saliva serine protease enhances dissemination of dengue virus into the mammalian host.
abstract: Dengue virus (DENV), a flavivirus of global importance, is transmitted to humans by mosquitoes. In this study, we developed in vitro and in vivo models of saliva-mediated enhancement of DENV infectivity. Serine protease activity in Aedes aegypti saliva augmented virus infectivity in vitro by proteolyzing extracellular matrix proteins, thereby increasing viral attachment to heparan sulfate proteoglycans and inducing cell migration. A serine protease inhibitor reduced saliva-mediated enhancement of DENV in vitro and in vivo, marked by a 100-fold reduction in DENV load in murine lymph nodes. A saliva-mediated infectivity enhancement screen of fractionated salivary gland extracts identified serine protease CLIPA3 as a putative cofactor, and short interfering RNA knockdown of CLIPA3 in mosquitoes demonstrated its role in influencing DENV infectivity. Molecules in mosquito saliva that facilitate viral infectivity in the vertebrate host provide novel targets that may aid in the prevention of disease.
authors.affiliation: Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Conway
authors.forename: Alan M
authors.initials: AM
authors.lastname: Watson
authors.forename: Tonya M
authors.initials: TM
authors.lastname: Colpitts
authors.forename: Srdjan M
authors.initials: SM
authors.lastname: Dragovic
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Li
authors.forename: Penghua
authors.initials: P
authors.lastname: Wang
authors.forename: Fabiana
authors.initials: F
authors.lastname: Feitosa
authors.forename: Denueve T
authors.initials: DT
authors.lastname: Shepherd
authors.forename: Kate D
authors.initials: KD
authors.lastname: Ryman
authors.forename: William B
authors.initials: WB
authors.lastname: Klimstra
authors.forename: John F
authors.initials: JF
authors.lastname: Anderson
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D009033:Culicidae; D017931:DNA Primers; D003716:Dengue Virus / Q000502:physiology*; D051379:Mice; D012463:Saliva / Q000201:enzymology*; D057057:Serine Proteases / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D017931:DNA Primers; D057057:Serine Proteases