title: Phospholipase D facilitates efficient entry of influenza virus, allowing escape from innate immune inhibition.
abstract: Lipid metabolism plays a fundamental role during influenza virus replication, although key regulators of lipid-dependent trafficking and virus production remain inadequately defined. This report demonstrates that infection by influenza virus stimulates phospholipase D (PLD) activity and that PLD co-localizes with influenza during infection. Both chemical inhibition and RNA interference of PLD delayed viral entry and reduced viral titers in vitro. Although there may be contributions by both major isoenzymes, the effects on viral infectivity appear to be more dependent on the PLD2 isoenzyme. In vivo, PLD2 inhibition reduced virus titer and correlated with significant increases in transcription of innate antiviral effectors. The reduction in viral titer downstream of PLD2 inhibition was dependent on Rig-I (retinoic acid-inducible gene-1), IRF3, and MxA (myxovirus resistance gene A) but not IRF7. Inhibition of PLD2 accelerated the accumulation of MxA in foci as early as 30 min postinfection. Together these data suggest that PLD facilitates the rapid endocytosis of influenza virus, permitting viral escape from innate immune detection and effectors that are capable of limiting lethal infection.
authors: From the Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, Department of Biological Sciences, University of Memphis, Memphis, Tennessee 38152.
authors: Thomas H
authors: TH
authors: Oguin
authors: Department of Veterinary Physiology and Biochemistry, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar 125004, Haryana, India.
authors: Shalini
authors: S
authors: Sharma
authors: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors: Amanda D
authors: AD
authors: Stuart
authors: From the Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678.
authors: Susu
authors: S
authors: Duan
authors: Departments of Pharmacology and.
authors: Sarah A
authors: SA
authors: Scott
authors: Departments of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0697.
authors: Carrie K
authors: CK
authors: Jones
authors: Departments of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0697.
authors: J Scott
authors: JS
authors: Daniels
authors: Departments of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0697 Department of Chemistry and The Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, and.
authors: Craig W
authors: CW
authors: Lindsley
authors: From the Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, Paul.Thomas@stjude.org.
authors: Paul G
authors: PG
authors: Thomas
authors: Departments of Pharmacology and Department of Chemistry and The Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, and Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600, alex.brown@vanderbilt.edu.
authors: H Alex
authors: HA
authors: Brown
mesh_terms: D002460:Cell Line; D004705:Endocytosis / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human / Q000235:genetics / Q000473:pathology / Q000821:virology*; D009975:Orthomyxoviridae / Q000235:genetics* / Q000472:pathogenicity; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D010743:Phospholipids; D034622:RNA Interference; D053586:Virus Internalization; D014779:Virus Replication / Q000235:genetics
chemical_list: D010743:Phospholipids; D010739:Phospholipase D
keywords: Antiviral Agent; Cell Signaling; Enzyme Inhibitor; Influenza Virus; Inhibitors; Phospholipase D; Phospholipid