An improved animal model for herpesvirus encephalitis in humans.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
23
01
2020
accepted:
29
02
2020
revised:
09
04
2020
pubmed:
1
4
2020
medline:
23
6
2020
entrez:
1
4
2020
Statut:
epublish
Résumé
Herpesviral encephalitis caused by Herpes Simplex Virus 1 (HSV-1) is one of the most devastating diseases in humans. Patients present with fever, mental status changes or seizures and when untreated, sequelae can be fatal. Herpes Simplex Encephalitis (HSE) is characterized by mainly unilateral necrotizing inflammation effacing the frontal and mesiotemporal lobes with rare involvement of the brainstem. HSV-1 is hypothesized to invade the CNS via the trigeminal or olfactory nerve, but viral tropism and the exact route of infection remain unclear. Several mouse models for HSE have been developed, but they mimic natural infection only inadequately. The porcine alphaherpesvirus Pseudorabies virus (PrV) is closely related to HSV-1 and Varicella Zoster Virus (VZV). While pigs can control productive infection, it is lethal in other susceptible animals associated with severe pruritus leading to automutilation. Here, we describe the first mutant PrV establishing productive infection in mice that the animals are able to control. After intranasal inoculation with a PrV mutant lacking tegument protein pUL21 and pUS3 kinase activity (PrV-ΔUL21/US3Δkin), nearly all mice survived despite extensive infection of the central nervous system. Neuroinvasion mainly occurred along the trigeminal pathway. Whereas trigeminal first and second order neurons and autonomic ganglia were positive early after intranasal infection, PrV-specific antigen was mainly detectable in the frontal, mesiotemporal and parietal lobes at later times, accompanied by a long lasting lymphohistiocytic meningoencephalitis. Despite this extensive infection, mice showed only mild to moderate clinical signs, developed alopecic skin lesions, or remained asymptomatic. Interestingly, most mice exhibited abnormalities in behavior and activity levels including slow movements, akinesia and stargazing. In summary, clinical signs, distribution of viral antigen and inflammatory pattern show striking analogies to human encephalitis caused by HSV-1 or VZV not observed in other animal models of disease.
Identifiants
pubmed: 32226043
doi: 10.1371/journal.ppat.1008445
pii: PPATHOGENS-D-20-00145
pmc: PMC7145201
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008445Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
J Biol Chem. 2015 Jun 19;290(25):15670-8
pubmed: 25907557
J Virol. 2013 Oct;87(19):10477-88
pubmed: 23903843
Neurology. 2014 Jan 7;82(1):90-2
pubmed: 24285619
Mediators Inflamm. 1995;4(1):5-15
pubmed: 18475609
Virology. 1995 Oct 1;212(2):466-73
pubmed: 7571416
J Virol. 2000 Nov;74(21):10063-73
pubmed: 11024135
Int J Infect Dis. 2019 Oct;87:92-99
pubmed: 31408708
Virus Res. 2013 May;173(2):436-40
pubmed: 23339898
J Gen Virol. 2001 Oct;82(Pt 10):2363-2371
pubmed: 11562530
J Clin Invest. 2017 Oct 2;127(10):3784-3795
pubmed: 28891812
J Virol. 2018 Oct 29;92(22):
pubmed: 30185591
BMC Infect Dis. 2018 May 25;18(1):238
pubmed: 29801466
J Neurol Neurosurg Psychiatry. 1985 Apr;48(4):297-301
pubmed: 3998736
Virology. 1989 Aug;171(2):623-5
pubmed: 2548334
Acta Neuropathol. 2016 Sep;132(3):433-51
pubmed: 27457581
J Virol. 2003 May;77(9):5339-51
pubmed: 12692236
Virology. 1994 Nov 1;204(2):616-25
pubmed: 7941329
J Infect Dis. 1982 Jun;145(6):829-36
pubmed: 6282983
Curr Neurol Neurosci Rep. 2013 Dec;13(12):414
pubmed: 24142852
Virology. 1959 Apr;7(4):394-407
pubmed: 13669311
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10410-5
pubmed: 11517326
Eur J Neurol. 2005 Jun;12(6):475-9
pubmed: 15885053
J Virol. 2018 Nov 27;92(24):
pubmed: 30258005
Semin Cutan Med Surg. 2011 Jun;30(2):87-92
pubmed: 21767768
Neurotherapeutics. 2016 Jul;13(3):493-508
pubmed: 27106239
J Clin Virol. 2014 Jan;59(1):1-3
pubmed: 23829964
Rev Neurol Dis. 2004 Fall;1(4):169-78
pubmed: 16400278
Clin Microbiol Infect. 2012 Aug;18(8):808-19
pubmed: 22085160
Virus Genes. 1995;10(3):217-26
pubmed: 8560783
J Neurosci. 2009 Nov 11;29(45):14223-35
pubmed: 19906970
J Infect Dis. 2009 Dec 15;200(12):1901-6
pubmed: 19919304
J Virol. 2003 Jan;77(2):1403-14
pubmed: 12502856
J Infect Dis. 2018 Sep 22;218(suppl_2):S107-S112
pubmed: 30247600
Virology. 2004 Feb 20;319(2):212-24
pubmed: 14980482
Neuropathol Appl Neurobiol. 1988 Sep-Oct;14(5):395-415
pubmed: 3200368
IDCases. 2016 Jun 22;5:29-31
pubmed: 27419072
J Neurovirol. 2017 Jun;23(3):394-403
pubmed: 28116674
Arch Neurol. 2009 Sep;66(9):1065-74
pubmed: 19752295
Future Virol. 2015 Jun;10(6):699-714
pubmed: 26213562
Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14632-6
pubmed: 21844356
Proc Natl Acad Sci U S A. 1981 Oct;78(10):6461-5
pubmed: 6273872
J Neuropathol Exp Neurol. 2014 Nov;73(11):999-1008
pubmed: 25289894
Viruses. 2018 May 15;10(5):
pubmed: 29762484
J Virol. 2004 Mar;78(6):2956-66
pubmed: 14990714
J Clin Microbiol. 2004 Feb;42(2):936-7
pubmed: 14766896
J Neurol. 1997 Apr;244(4):239-45
pubmed: 9112592
PLoS Pathog. 2019 Nov 1;15(11):e1008087
pubmed: 31675371
J Neurovirol. 2003 Jun;9(3):404-7
pubmed: 12775423
Clin Neuropathol. 1995 Jan-Feb;14(1):45-50
pubmed: 7729081
Vet Res. 2001 Jan-Feb;32(1):47-54
pubmed: 11254176
PLoS One. 2013 Aug 12;8(8):e72050
pubmed: 23951282
Virology. 1994 Dec;205(2):511-8
pubmed: 7975253
Cell Death Differ. 2003 Dec;10(12):1320-8
pubmed: 12934063
J Gen Virol. 2017 Mar;98(3):447-460
pubmed: 27902351
Case Rep Neurol. 2017 Aug 8;9(2):188-194
pubmed: 28966586
J Infect. 2015 Sep;71(3):281-93
pubmed: 26073188
J Virol. 2008 Jul;82(14):7078-88
pubmed: 18480436
J Virol. 2007 Oct;81(19):10242-8
pubmed: 17634220
J Virol. 2005 Feb;79(3):1510-22
pubmed: 15650177
J Virol. 2020 Mar 17;94(7):
pubmed: 31941788
Yale J Biol Med. 1984 Sep-Oct;57(5):751-5
pubmed: 6098083
Exp Cell Res. 2003 Nov 15;291(1):242-50
pubmed: 14597423
J Virol. 2007 Jan;81(2):1048-51
pubmed: 17079290
Rev Neurosci. 2018 Feb 23;29(2):115-123
pubmed: 29116936
J Neurovirol. 2015 Feb;21(1):8-23
pubmed: 25388226
Clin Infect Dis. 2002 Aug 1;35(3):254-60
pubmed: 12115090
J Virol. 1994 May;68(5):2929-36
pubmed: 8151763
J Virol. 2019 Mar 21;93(7):
pubmed: 30651360
Mol Vis. 2012;18:2711-6
pubmed: 23213272
J Virol. 2009 Feb;83(3):1173-83
pubmed: 19019952
J Neurol. 2010 Sep;257(9):1432-7
pubmed: 20495814
J Infect Dis. 1991 Apr;163(4):720-7
pubmed: 1849158
J Virol. 1992 Dec;66(12):7096-103
pubmed: 1331512
Vet Res. 2000 Jan-Feb;31(1):99-115
pubmed: 10726640
J Neurovirol. 2005 Apr;11(2):129-37
pubmed: 16036791
Indian J Dermatol. 2014 Jan;59(1):75-6
pubmed: 24470665
Lancet. 2014 Nov 8;384(9955):1698
pubmed: 24999086
Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7891-6
pubmed: 9223283
J Neurol Neurosurg Psychiatry. 1997 Sep;63(3):321-6
pubmed: 9328248
Mamm Genome. 2018 Aug;29(7-8):425-445
pubmed: 30167845
J Virol. 1987 Sep;61(9):2896-901
pubmed: 3039176
Adv Exp Med Biol. 2018;1045:45-62
pubmed: 29896662
Nat Med. 2013 Apr;19(4):458-64
pubmed: 23455712
J Virol. 2006 Jun;80(11):5571-6
pubmed: 16699038
J Gen Virol. 1994 Sep;75 ( Pt 9):2319-27
pubmed: 8077930
J Virol. 2015 Jul;89(13):6646-55
pubmed: 25878107
Neurol Clin. 2018 Nov;36(4):725-738
pubmed: 30366551
F1000Res. 2018 Oct 31;7:
pubmed: 30443341
J R Soc Med. 2001 Mar;94(3):135-7
pubmed: 11285797
Int J Infect Dis. 2019 Dec;89:51-54
pubmed: 31562933
J Virol. 2012 Jun;86(12):7003-7
pubmed: 22496211
Neuropathol Appl Neurobiol. 1991 Oct;17(5):375-82
pubmed: 1661857
Front Aging Neurosci. 2018 Oct 19;10:324
pubmed: 30405395
Scand J Immunol. 2004 Dec;60(6):592-9
pubmed: 15584970
Adv Virus Res. 1998;51:237-347
pubmed: 9891589
J Infect Dis. 2007 Sep 15;196(6):853-60
pubmed: 17703415
J Neurol Sci. 1982 May;54(2):209-26
pubmed: 6284882
J Virol. 2003 Jun;77(11):6567-73
pubmed: 12743316
J Pathol Transl Med. 2016 Nov;50(6):411-418
pubmed: 27809448
J Neurol Neurosurg Psychiatry. 1979 Nov;42(11):983-7
pubmed: 228010
Viral Immunol. 2006 Summer;19(3):391-408
pubmed: 16987059
Clin Infect Dis. 1995 Feb;20(2):414-20
pubmed: 7742450
Virology. 2005 Jan 5;331(1):144-50
pubmed: 15582661
Br Med J. 1980 Nov 22;281(6252):1392
pubmed: 7437807
Nat Clin Pract Neurol. 2007 Feb;3(2):82-94
pubmed: 17279082
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17916-20
pubmed: 19805039
J Neuroinflammation. 2012 Dec 17;9:270
pubmed: 23244217