title: ERK signaling couples nutrient status to antiviral defense in the insect gut.
abstract: A unique facet of arthropod-borne virus (arbovirus) infection is that the pathogens are orally acquired by an insect vector during the taking of a blood meal, which directly links nutrient acquisition and pathogen challenge. We show that the nutrient responsive ERK pathway is both induced by and restricts disparate arboviruses in Drosophila intestines, providing insight into the molecular determinants of the antiviral "midgut barrier." Wild-type flies are refractory to oral infection by arboviruses, including Sindbis virus and vesicular stomatitis virus, but this innate restriction can be overcome chemically by oral administration of an ERK pathway inhibitor or genetically via the specific loss of ERK in Drosophila intestinal epithelial cells. In addition, we found that vertebrate insulin, which activates ERK in the mosquito gut during a blood meal, restricts viral infection in Drosophila cells and against viral invasion of the insect gut epithelium. We find that ERK's antiviral signaling activity is likely conserved in Aedes mosquitoes, because genetic or pharmacologic manipulation of the ERK pathway affects viral infection of mosquito cells. These studies demonstrate that ERK signaling has a broadly antiviral role in insects and suggest that insects take advantage of cross-species signals in the meal to trigger antiviral immunity.
authors: Department of Microbiology, Penn Genome Frontiers Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
authors: Jie
authors: J
authors: Xu
authors: Kaycie
authors: K
authors: Hopkins
authors: Leah
authors: L
authors: Sabin
authors: Ari
authors: A
authors: Yasunaga
authors: Harry
authors: H
authors: Subramanian
authors: Ian
authors: I
authors: Lamborn
authors: Beth
authors: B
authors: Gordesky-Gold
authors: Sara
authors: S
authors: Cherry
mesh_terms: D000330:Aedes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D001103:Arboviruses / Q000276:immunology* / Q000472:pathogenicity; D004064:Digestive System / Q000276:immunology / Q000378:metabolism / Q000821:virology; D004331:Drosophila melanogaster / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology; D007113:Immunity, Innate; D007303:Insect Vectors / Q000276:immunology / Q000378:metabolism / Q000821:virology; D007328:Insulin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D034622:RNA Interference
chemical_list: D007328:Insulin
keywords: enterocytes; innate immunity
references: J Innate Immun. 2012;4(3):273-83
references: 22237424
references: Curr Opin Immunol. 2010 Feb;22(1):4-9
references: 20137906
references: Fly (Austin). 2010 Jan-Mar;4(1):40-7
references: 20383054
references: PLoS Pathog. 2012 Sep;8(9):e1002897
references: 23028310
references: J Biol Chem. 1998 Jul 17;273(29):18623-32
references: 9660836
references: Fly (Austin). 2011 Jul-Sep;5(3):247-54
references: 21738010
references: Arch Med Res. 2002 Jul-Aug;33(4):379-88
references: 12234528
references: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17841-6
references: 19805194
references: Insect Mol Biol. 2003 Apr;12(2):107-16
references: 12653932
references: Cell Stem Cell. 2009 Jan 9;4(1):49-61
references: 19128792
references: J Virol. 2011 Apr;85(7):3330-40
references: 21270146
references: BMC Biol. 2010 Dec 22;8:152
references: 21176204
references: Nature. 2006 Dec 14;444(7121):860-7
references: 17167474
references: Nature. 2010 Feb 11;463(7282):818-22
references: 20081832
references: Immunol Rev. 2011 Mar;240(1):129-40
references: 21349091
references: J Virol. 2007 Dec;81(24):13700-9
references: 17913811
references: Annu Rev Immunol. 2007;25:697-743
references: 17201680
references: Dev Comp Immunol. 2010 Jun;34(6):625-9
references: 20079370
references: Vector Borne Zoonotic Dis. 2004 Summer;4(2):109-22
references: 15228811
references: Nature. 2008 Jul 31;454(7204):592-3
references: 18668098
references: Genes Dev. 1996 Nov 1;10(21):2745-58
references: 8946915
references: Cell Host Microbe. 2012 Oct 18;12(4):531-43
references: 23084920
references: Nat Rev Microbiol. 2004 Oct;2(10):789-801
references: 15378043
references: Science. 2002 Dec 6;298(5600):1911-2
references: 12471242
references: Cytokine. 2009 Dec;48(3):161-9
references: 19740675
references: Genes Dev. 2004 Mar 1;18(5):584-94
references: 15037551
references: J Med Entomol. 1993 Mar;30(2):332-7
references: 8384663
references: Genes Dev. 2005 Feb 15;19(4):445-52
references: 15713840
references: EMBO J. 2011 Mar 16;30(6):1123-36
references: 21297578
references: PLoS Genet. 2011 Dec;7(12):e1002429
references: 22242005
references: Cell. 2009 Jun 26;137(7):1343-55
references: 19563763
references: Nat Immunol. 2004 Jan;5(1):81-7
references: 14691479
references: Infect Immun. 2012 Jun;80(6):2141-9
references: 22473605
references: BMC Microbiol. 2007 Jan 30;7:9
references: 17263893
references: Ann Microbiol (Paris). 1976 May-Jun;127(4):529-44
references: 823856
references: Nature. 2009 Apr 23;458(7241):1047-50
references: 19396146
references: J Mol Biol. 1994 Jun 10;239(3):347-56
references: 8201616
references: Bioessays. 2000 May;22(5):469-80
references: 10797487
references: Antioxid Redox Signal. 2011 Mar 15;14(6):943-55
references: 21126166
references: Methods Mol Biol. 2011;721:375-82
references: 21431698
references: Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20774-9
references: 21076039
references: Cell Host Microbe. 2011 Aug 18;10(2):97-104
references: 21843867
references: Am J Trop Med Hyg. 1999 Feb;60(2):319-21
references: 10072159
references: PLoS Pathog. 2008 Jul 04;4(7):e1000098
references: 18604274
references: Nature. 2006 Jan 26;439(7075):470-4
references: 16340960
references: J Exp Biol. 2008 Mar;211(Pt 5):741-8
references: 18281336
references: Nature. 2006 Nov 9;444(7116):230-4
references: 17086199
references: Cell. 2009 Jul 23;138(2):340-51
references: 19632183
references: Annu Rev Entomol. 1983;28:229-62
references: 6131642
references: Nat Immunol. 2006 Sep;7(9):911-7
references: 16924255
references: J Invertebr Pathol. 1995 May;65(3):243-7
references: 7745279
references: Science. 2002 Oct 4;298(5591):159-65
references: 12364793
references: PLoS Pathog. 2009 Apr;5(4):e1000366
references: 19343212
references: J Chem Biol. 2011 Apr;4(2):55-68
references: 22190992