title: Influence of perineurial cells and Toll-like receptors 2 and 9 on Herpes simplex type 1 entry to the central nervous system in rat encephalitis.
abstract: Herpes simplex encephalitis (HSE) is a rare disease with high mortality and significant morbidity among survivors. We have previously shown that susceptibility to HSE was host-strain dependent, as severe, lethal HSE developed after injection of human Herpes simplex type 1 virus (HSV-1) into the whiskers area of DA rats, whereas PVG rats remained completely asymptomatic. In the present study we investigated the early immunokinetics in these strains to address the underlying molecular mechanisms for the observed difference. The virus distribution and the immunological responses were compared in the whiskers area, trigeminal ganglia and brain stem after 12 hours and the first four days following infection using immunohistochemistry and qRT-PCR. A conspicuous immunopathological finding was a strain-dependent difference in the spread of the HSV-1 virus to the trigeminal ganglia, only seen in DA rats already from 12 hpi. In the whiskers area infected perineurial cells were abundant in the susceptible DA strain after 2 dpi, whereas in the resistant PVG rats HSV-1 spread was confined only to the epineurium. In both strains activation of Iba1(+)/ED1(+) phagocytic cells followed the distribution pattern of HSV-1 staining, which was visible already at 12 hours after infection. Notably, in PVG rats higher mRNA expression of Toll-like receptors (Tlr) -2 and -9, together with increased staining for Iba1/ED1 was detected in the whiskers area. In contrast, all other Tlr-pathway markers were expressed at higher levels in the susceptible DA rats. Our data demonstrate the novel observation that genetically encoded properties of the host nerve and perineurial cells, recruitment of phagocyting cells together with the low expression of Tlr2 and -9 in the periphery define the susceptibility to HSV-1 entry into the nervous system.
authors.affiliation: Department of Medicine Solna, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Biborka
authors.initials: B
authors.lastname: Bereczky-Veress
authors.forename: Nada
authors.initials: N
authors.lastname: Abdelmagid
authors.forename: Fredrik
authors.initials: F
authors.lastname: Piehl
authors.forename: Tomas
authors.initials: T
authors.lastname: Bergström
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Birgit
authors.initials: B
authors.lastname: Sköldenberg
authors.forename: Margarita
authors.initials: M
authors.lastname: Diez
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D018792:Encephalitis, Viral / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D005786:Gene Expression Regulation / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000821:virology; D007700:Kinetics; D008264:Macrophages / Q000276:immunology / Q000821:virology; D008297:Male; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012583:Schwann Cells / Q000473:pathology / Q000821:virology; D015398:Signal Transduction / Q000276:immunology; D013045:Species Specificity; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000473:pathology / Q000821:virology; D014738:Vibrissae / Q000294:innervation / Q000821:virology; D053586:Virus Internalization
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9
references.citation: Lancet. 1984 Sep 29;2(8405):707-11
references.pmid: 6148470
references.citation: Front Biosci. 2008 May 01;13:4862-72
references.pmid: 18508551
references.citation: J Cereb Blood Flow Metab. 2010 Mar;30(3):603-15
references.pmid: 19861972
references.citation: J Neuropathol Exp Neurol. 2002 Nov;61(11):1013-21
references.pmid: 12430718
references.citation: J Neurol. 2006 Feb;253(2):163-70
references.pmid: 16222428
references.citation: Gen Cytochem Methods. 1958;1:399-422
references.pmid: 13574437
references.citation: Science. 2006 Oct 13;314(5797):308-12
references.pmid: 16973841
references.citation: Curr Opin Immunol. 2008 Aug;20(4):420-5
references.pmid: 18625310
references.citation: J Immunol. 2010 Jun 15;184(12):7010-21
references.pmid: 20483728
references.citation: Neuroscience. 2002;115(1):321-9
references.pmid: 12401344
references.citation: J Neurol. 2009 Aug;256(8):1243-51
references.pmid: 19353228
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17343-8
references.pmid: 17085599
references.citation: J Gen Virol. 1990 Feb;71 ( Pt 2):405-10
references.pmid: 2155294
references.citation: J Cell Biol. 2007 Apr 23;177(2):265-75
references.pmid: 17452530
references.citation: J Immunol. 2006 Nov 15;177(10):7094-102
references.pmid: 17082626
references.citation: Science. 2007 Sep 14;317(5844):1522-7
references.pmid: 17872438
references.citation: Neuroscience. 1997 Nov;81(1):255-62
references.pmid: 9300418
references.citation: J Neurosci Methods. 1980 Dec;3(2):129-49
references.pmid: 6110810
references.citation: Blood. 2004 Feb 15;103(4):1433-7
references.pmid: 14563635
references.citation: Virology. 2010 May 10;400(2):248-58
references.pmid: 20199790
references.citation: J Virol. 2007 Oct;81(20):11128-38
references.pmid: 17686871
references.citation: J Neurovirol. 2008 Apr;14(2):102-18
references.pmid: 18444082
references.citation: J Neurocytol. 1984 Dec;13(6):923-34
references.pmid: 6398831
references.citation: Am J Pathol. 2005 May;166(5):1419-26
references.pmid: 15855642
references.citation: J Virol. 2003 Apr;77(8):4588-96
references.pmid: 12663765
references.citation: J Neuroimmunol. 2009 Aug 18;213(1-2):26-30
references.pmid: 19564053
references.citation: J Infect Dis. 1993 Nov;168(5):1248-52
references.pmid: 8228358
references.citation: J Immunol. 2008 Dec 15;181(12):8604-12
references.pmid: 19050280
references.citation: J Cell Sci. 2006 Oct 1;119(Pt 19):3981-93
references.pmid: 16988027
references.citation: Nature. 2005 Apr 7;434(7034):772-7
references.pmid: 15800576
references.citation: Am J Pathol. 1993 Aug;143(2):410-8
references.pmid: 8102030
references.citation: Glia. 2010 Nov 1;58(14):1701-9
references.pmid: 20578041