Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape.
Animals
Astroviridae Infections
/ immunology
Caco-2 Cells
Cell Line
Chlorocebus aethiops
Enterocytes
/ virology
Gastroenteritis
/ virology
Humans
Immunity, Innate
/ immunology
Interferons
/ immunology
Intestinal Mucosa
/ cytology
Intestine, Small
/ cytology
Mamastrovirus
/ genetics
Vero Cells
Viral Tropism
/ genetics
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
10
05
2019
accepted:
30
08
2019
revised:
13
01
2020
pubmed:
2
11
2019
medline:
6
2
2020
entrez:
1
11
2019
Statut:
epublish
Résumé
Human astroviruses (HAstV) are understudied positive-strand RNA viruses that cause gastroenteritis mostly in children and the elderly. Three clades of astroviruses, classic, MLB-type and VA-type have been reported in humans. One limitation towards a better understanding of these viruses has been the lack of a physiologically relevant cell culture model that supports growth of all clades of HAstV. Herein, we demonstrate infection of HAstV strains belonging to all three clades in epithelium-only human intestinal enteroids (HIE) isolated from biopsy-derived intestinal crypts. A detailed investigation of infection of VA1, a member of the non-canonical HAstV-VA/HMO clade, showed robust replication in HIE derived from different patients and from different intestinal regions independent of the cellular differentiation status. Flow cytometry and immunofluorescence analysis revealed that VA1 infects several cell types, including intestinal progenitor cells and mature enterocytes, in HIE cultures. RNA profiling of VA1-infected HIE uncovered that the host response to infection is dominated by interferon (IFN)-mediated innate immune responses. A comparison of the antiviral host response in non-transformed HIE and transformed human colon carcinoma Caco-2 cells highlighted significant differences between these cells, including an increased magnitude of the response in HIE. Additional studies confirmed the sensitivity of VA1 to exogenous IFNs, and indicated that the endogenous IFN response of HIE to curtail the growth of strains from all three clades. Genotypic variation in the permissiveness of different HIE lines to HAstV could be overcome by pharmacologic inhibition of JAK/STAT signaling. Collectively, our data identify HIE as a universal infection model for HAstV and an improved model of the intestinal epithelium to investigate enteric virus-host interactions.
Identifiants
pubmed: 31671153
doi: 10.1371/journal.ppat.1008057
pii: PPATHOGENS-D-19-00871
pmc: PMC6957189
doi:
Substances chimiques
Interferons
9008-11-1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008057Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR000433
Pays : United States
Organisme : Wellcome Trust
ID : 207498/Z/17/Z
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : U19 AI116482
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK085532
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS101371
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK103141
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034933
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI135254
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK085532
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R21 AI141835
Pays : United States
Organisme : NIAID NIH HHS
ID : K08 AI132745
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Clin Infect Dis. 2015 Mar 15;60(6):881-8
pubmed: 25572899
Stem Cells. 2014 May;32(5):1083-91
pubmed: 24496776
J Virol. 2019 Jun 14;93(13):
pubmed: 31019055
Lancet. 1975 Jul 19;2(7925):124
pubmed: 49708
Emerg Infect Dis. 2010 Jun;16(6):918-25
pubmed: 20507741
Viruses. 2016 Dec 30;9(1):
pubmed: 28042824
Arch Virol. 1979;60(3-4):217-26
pubmed: 116623
mBio. 2019 Mar 12;10(2):
pubmed: 30862747
Stem Cells. 2013 Sep;31(9):2024-30
pubmed: 23553902
Science. 2015 Jan 16;347(6219):269-73
pubmed: 25431489
J Virol. 2015 Nov 18;90(3):1499-506
pubmed: 26581993
PLoS One. 2012;7(6):e27735
pubmed: 22719819
J Virol. 2013 Aug;87(16):8843-52
pubmed: 23740996
Arch Virol. 2000;145(9):1847-56
pubmed: 11043945
PLoS One. 2015 Sep 28;10(9):e0138531
pubmed: 26414184
Nat Immunol. 2014 Aug;15(8):717-26
pubmed: 24952503
Antimicrob Agents Chemother. 2011 Aug;55(8):3854-60
pubmed: 21628542
Gastroenterology. 2011 Nov;141(5):1762-72
pubmed: 21889923
Curr Protoc Microbiol. 2014 May 01;33:15K.2.1-61
pubmed: 24789596
OMICS. 2012 May;16(5):284-7
pubmed: 22455463
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nat Biotechnol. 2016 May;34(5):525-7
pubmed: 27043002
J Cell Biol. 2018 May 7;217(5):1667-1685
pubmed: 29599208
J Antimicrob Chemother. 2015 Jan;70(1):190-7
pubmed: 25228588
Front Immunol. 2017 Jun 30;8:749
pubmed: 28713375
J Clin Pathol. 2004 Sep;57(9):1001-3
pubmed: 15333670
Nat Protoc. 2013 Dec;8(12):2471-82
pubmed: 24232249
PLoS One. 2015 Apr 02;10(4):e0123087
pubmed: 25837699
PLoS Pathog. 2011 Jul;7(7):e1002115
pubmed: 21779163
Gastroenterology. 2009 Jul;137(1):15-7
pubmed: 19450592
J Virol. 2013 Nov;87(21):11798-805
pubmed: 23986582
J Virol. 2013 Mar;87(6):3261-70
pubmed: 23302870
J Virol. 2007 Nov;81(21):11937-45
pubmed: 17699569
mBio. 2019 Jul 9;10(4):
pubmed: 31289185
J Virol. 2015 Dec 09;90(4):1988-96
pubmed: 26656701
Development. 2018 Mar 14;145(6):
pubmed: 29467240
Antiviral Res. 2016 Aug;132:46-9
pubmed: 27210811
Nucleic Acids Res. 2015 Jan;43(Database issue):D1049-56
pubmed: 25428369
Curr Opin Neurobiol. 2007 Feb;17(1):43-52
pubmed: 17275284
J Virol. 2014 Mar;88(5):2452-60
pubmed: 24335315
Nat Microbiol. 2019 Jun;4(6):1006-1013
pubmed: 30833734
PLoS Pathog. 2013;9(11):e1003773
pubmed: 24278020
J Virol. 2017 Sep 12;91(19):null
pubmed: 28701405
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6110-5
pubmed: 15071180
Nat Microbiol. 2019 Jul;4(7):1120-1128
pubmed: 30936486
Biochem Biophys Res Commun. 2012 Nov 2;427(4):796-800
pubmed: 23063849
J Virol. 2015 Oct 07;90(1):43-56
pubmed: 26446608
Clin Microbiol Rev. 2014 Oct;27(4):1048-74
pubmed: 25278582
J Gen Virol. 2002 Jul;83(Pt 7):1691-5
pubmed: 12075088
J Virol. 2018 Apr 13;92(9):
pubmed: 29467318
Arch Virol. 1990;113(1-2):73-81
pubmed: 2117433
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20667-72
pubmed: 23188796
J Virol. 2009 Oct;83(20):10836-9
pubmed: 19706703
Sci Rep. 2018 Sep 21;8(1):14174
pubmed: 30242205
J Clin Microbiol. 2010 Sep;48(9):3416-8
pubmed: 20573860
J Immunol. 2012 Sep 15;189(6):2784-92
pubmed: 22904308
PLoS Pathog. 2012;8(7):e1002783
pubmed: 22792064
Emerg Infect Dis. 2011 Nov;17(11):2050-2
pubmed: 22099095
Methods Mol Biol. 2019;1576:229-247
pubmed: 28361480
mBio. 2012 Jul 03;3(4):e00159-12
pubmed: 22761392
PLoS Pathog. 2015 Apr 07;11(4):e1004782
pubmed: 25849543
Science. 2013 Jun 7;340(6137):1190-4
pubmed: 23744940
J Gen Virol. 2014 Sep;95(Pt 9):1958-68
pubmed: 24899153
Viruses. 2016 Nov 01;8(11):
pubmed: 27809273
Cell Mol Gastroenterol Hepatol. 2017 Dec 09;5(3):241-251
pubmed: 29675450
Cell Mol Gastroenterol Hepatol. 2019;7(3):686-688.e5
pubmed: 30543870
Science. 2016 Sep 23;353(6306):1387-1393
pubmed: 27562956
Curr Opin Immunol. 2017 Oct;48:15-22
pubmed: 28756233
Nucleic Acids Res. 2018 Jan 4;46(D1):D649-D655
pubmed: 29145629
Viruses. 2017 Feb 18;9(2):
pubmed: 28218712
Nat Microbiol. 2019 Jun;4(6):914-924
pubmed: 30936491
Cell Mol Gastroenterol Hepatol. 2018 May 30;6(2):218-222.e7
pubmed: 30105282
Am J Pathol. 1998 Sep;153(3):937-44
pubmed: 9736042
Cytometry. 1996 Jan 1;23(1):72-7
pubmed: 14650444
Mol Biosyst. 2016 Feb;12(2):477-9
pubmed: 26661513
Nat Immunol. 2015 Jul;16(7):698-707
pubmed: 26006013
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E570-E579
pubmed: 28069942
J Gen Virol. 1980 Jul;49(1):71-82
pubmed: 6775050
PLoS One. 2011 Apr 22;6(4):e18133
pubmed: 21526113
Viruses. 2018 Mar 10;10(3):
pubmed: 29534451
Histochem Cell Biol. 1998 Feb;109(2):161-5
pubmed: 9504776
Annu Rev Physiol. 2017 Feb 10;79:291-312
pubmed: 28192061
Nat Biotechnol. 2010 Feb;28(2):167-71
pubmed: 20118917
Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1672-1677
pubmed: 28137842