title: Inhibition of cellular autophagy deranges dengue virion maturation.
abstract: Autophagy is an important component of the innate immune response, directly destroying many intracellular pathogens. However, some pathogens, including several RNA viruses, subvert the autophagy pathway, or components of the pathway, to facilitate their replication. In the present study, the effect of inhibiting autophagy on the growth of dengue virus was tested using a novel inhibitor, spautin-1 (specific and potent autophagy inhibitor 1). Inhibition of autophagy by spautin-1 generated heat-sensitive, noninfectious dengue virus particles, revealing a large effect of components of the autophagy pathway on viral maturation. A smaller effect on viral RNA accumulation was also observed. Conversely, stimulation of autophagy resulted in increased viral titers and pathogenicity in the mouse. We conclude that the presence of functional autophagy components facilitates viral RNA replication and, more importantly, is required for infectious dengue virus production. Pharmacological inhibition of host processes is an attractive antiviral strategy to avoid selection of treatment-resistant variants, and inhibitors of autophagy may prove to be valuable therapeutics against dengue virus infection and pathogenesis.
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mateo
authors.forename: Claude M
authors.initials: CM
authors.lastname: Nagamine
authors.forename: Jeannie
authors.initials: J
authors.lastname: Spagnolo
authors.forename: Ernesto
authors.initials: E
authors.lastname: Méndez
authors.forename: Michael
authors.initials: M
authors.lastname: Rahe
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Karla
authors.initials: K
authors.lastname: Kirkegaard
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D003715:Dengue / Q000473:pathology / Q000821:virology; D003716:Dengue Virus / Q000254:growth & development / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D019065:Virus Assembly; D014779:Virus Replication