title: Two Modes of the Axonal Interferon Response Limit Alphaherpesvirus Neuroinvasion.
abstract: Infection by alphaherpesviruses, including herpes simplex virus (HSV) and pseudorabies virus (PRV), typically begins at epithelial surfaces and continues into the peripheral nervous system (PNS). Inflammatory responses are induced at the infected peripheral site prior to invasion of the PNS. When the peripheral tissue is first infected, only the innervating axons are exposed to this inflammatory milieu, which includes the interferons (IFNs). The fundamental question is how do PNS cell bodies respond to these distant, potentially damaging events experienced by axons. Using compartmented cultures that physically separate neuron axons from cell bodies, we found that pretreating isolated axons with beta interferon (IFN-β) or gamma interferon (IFN-γ) significantly diminished the number of herpes simplex virus 1 (HSV-1) and PRV particles moving in axons toward the cell bodies in a receptor-dependent manner. Exposing axons to IFN-β induced STAT1 phosphorylation (p-STAT1) only in axons, while exposure of axons to IFN-γ induced p-STAT1 accumulation in distant cell body nuclei. Blocking transcription in cell bodies eliminated antiviral effects induced by IFN-γ, but not those induced by IFN-β. Proteomic analysis of IFN-β- or IFN-γ-treated axons identified several differentially regulated proteins. Therefore, unlike treatment with IFN-γ, IFN-β induces a noncanonical, local antiviral response in axons. The activation of a local IFN response in axons represents a new paradigm for cytokine control of neuroinvasion.
  
  
  OBJECTIVE
  Neurons are highly polarized cells with long axonal processes that connect to distant targets. PNS axons that innervate peripheral tissues are exposed to various situations that follow infection, inflammation, and damage of the tissue. After viral infection in the periphery, axons represent potential front-line barriers to PNS infection and damage. Indeed, most viral infections do not spread to the PNS, yet the mechanisms responsible are not well studied. We devised an experimental system to study how axons respond to inflammatory cytokines that would be produced by infected tissues. We found that axons respond differentially to type I and type II interferons. The response to type I interferon (IFN-β) is a rapid axon-only response. The response to type II interferon (IFN-γ) involves long-distance signaling to the PNS cell body. These responses to two interferons erect an efficient and rapid barrier to PNS infection.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, USA.
authors.forename: Ren
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, USA.
authors.forename: Orkide O
authors.initials: OO
authors.lastname: Koyuncu
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Greco
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Diner
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
authors.forename: Ileana M
authors.initials: IM
authors.lastname: Cristea
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey, USA lenquist@princeton.edu.
authors.forename: Lynn W
authors.initials: LW
authors.lastname: Enquist
mesh_terms: D000818:Animals; D001369:Axons / Q000276:immunology* / Q000821:virology*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D018259:Herpesvirus 1, Human / Q000276:immunology*; D011558:Herpesvirus 1, Suid / Q000276:immunology*; D016899:Interferon-beta / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D016899:Interferon-beta; D007371:Interferon-gamma
references.citation: J Neurochem. 2007 Oct;103(1):288-302
references.pmid: 17608645
references.citation: Nat Rev Immunol. 2014 Jan;14(1):36-49
references.pmid: 24362405
references.citation: PLoS One. 2012;7(8):e44177
references.pmid: 22952920
references.citation: MBio. 2015;6(2). pii: e00276-15. doi: 10.1128/mBio.00276-15
references.pmid: 25805728
references.citation: J Virol. 1995 Aug;69(8):4792-6
references.pmid: 7609046
references.citation: J Biol Chem. 2009 Sep 4;284(36):24341-53
references.pmid: 19553685
references.citation: Arch Gesamte Virusforsch. 1974;44(2):150-2
references.pmid: 4858012
references.citation: Arch Virol. 1989;104(1-2):153-6
references.pmid: 2538109
references.citation: Curr Protoc Cell Biol. 2009 Jun;Chapter 26:Unit 26.4
references.pmid: 19499506
references.citation: Eur J Biochem. 2000 Oct;267(20):6264-75
references.pmid: 11012681
references.citation: Proteomics. 2004 Feb;4(2):339-46
references.pmid: 14760703
references.citation: EMBO J. 2012 Mar 21;31(6):1350-63
references.pmid: 22246183
references.citation: Cell Host Microbe. 2013 Jan 16;13(1):54-66
references.pmid: 23332155
references.citation: Exp Cell Biol. 1989;57(2):67-72
references.pmid: 2504627
references.citation: Nat Rev Neurosci. 2012 May;13(5):308-24
references.pmid: 22498899
references.citation: Nat Genet. 2002 Sep;32(1):116-27
references.pmid: 12195424
references.citation: J Vis Exp. 2013;(78). doi: 10.3791/50723
references.pmid: 23978901
references.citation: J Comp Neurol. 2004 Jul 5;474(4):535-45
references.pmid: 15174071
references.citation: Neuron. 1997 Dec;19(6):1187-99
references.pmid: 9427243
references.citation: J Biol Chem. 2003 Sep 5;278(36):33637-44
references.pmid: 12807916
references.citation: J Virol. 2005 Apr;79(7):3903-19
references.pmid: 15767393
references.citation: Annu Rev Microbiol. 2013;67:355-74
references.pmid: 24024635
references.citation: Neuron. 2013 Oct 30;80(3):648-57
references.pmid: 24183017
references.citation: J Cell Sci. 2000 Jun;113 ( Pt 12):2285-97
references.pmid: 10825300
references.citation: J Interferon Cytokine Res. 2006 Nov;26(11):804-19
references.pmid: 17115899
references.citation: Front Immunol. 2015 May 08;6:208
references.pmid: 26005444
references.citation: J Cell Biol. 2015 Oct 26;211(2):323-37
references.pmid: 26504169
references.citation: Exp Cell Res. 2014 Nov 1;328(2):267-75
references.pmid: 25107381
references.citation: Annu Rev Microbiol. 2012;66:153-76
references.pmid: 22726218
references.citation: Neuron. 2003 Dec 18;40(6):1095-104
references.pmid: 14687545
references.citation: J Virol. 2009 Feb;83(3):1173-83
references.pmid: 19019952
references.citation: Biochem Biophys Res Commun. 2001 Oct 19;288(1):252-7
references.pmid: 11594781
references.citation: Nat Rev Mol Cell Biol. 2008 Apr;9(4):309-22
references.pmid: 18322465
references.citation: Nat Cell Biol. 2008 Feb;10(2):149-59
references.pmid: 18193038
references.citation: Bioessays. 2004 Feb;26(2):141-50
references.pmid: 14745832
references.citation: PLoS Pathog. 2015 Jul;11(7):e1005028
references.pmid: 26153886
references.citation: Annu Rev Immunol. 2014;32:513-45
references.pmid: 24555472
references.citation: Eur J Haematol. 2001 Aug;67(2):63-71
references.pmid: 11722592
references.citation: Cell Host Microbe. 2013 Apr 17;13(4):379-93
references.pmid: 23601101
references.citation: Cell Death Dis. 2011;2:e175
references.pmid: 21697950
references.citation: J Neurosci. 2013 Aug 7;33(32):13190-203
references.pmid: 23926272
references.citation: Methods Mol Biol. 2014;1144:43-62
references.pmid: 24671676
references.citation: J Biol Chem. 1996 Mar 8;271(10):5790-4
references.pmid: 8621447
references.citation: Arch Virol. 1979;60(1):13-23
references.pmid: 226030
references.citation: Front Immunol. 2014 Feb 06;5:15
references.pmid: 24567732
references.citation: Diabetologia. 2004 Jul;47(7):1292-302
references.pmid: 15248046
references.citation: EMBO J. 2001 Aug 1;20(15):4041-54
references.pmid: 11483508
references.citation: Cell Mol Life Sci. 2008 Jun;65(11):1653-68
references.pmid: 18351291