Polarized lung inflammation and Tie2/angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection.
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
26
07
2019
accepted:
29
01
2020
revised:
12
03
2020
pubmed:
3
3
2020
medline:
13
5
2020
entrez:
3
3
2020
Statut:
epublish
Résumé
Orientia tsutsugamushi infection can cause acute lung injury and high mortality in humans; however, the underlying mechanisms are unclear. Here, we tested a hypothesis that dysregulated pulmonary inflammation and Tie2-mediated endothelial malfunction contribute to lung damage. Using a murine model of lethal O. tsutsugamushi infection, we demonstrated pathological characteristics of vascular activation and tissue damage: 1) a significant increase of ICAM-1 and angiopoietin-2 (Ang2) proteins in inflamed tissues and lung-derived endothelial cells (EC), 2) a progressive loss of endothelial quiescent and junction proteins (Ang1, VE-cadherin/CD144, occuludin), and 3) a profound impairment of Tie2 receptor at the transcriptional and functional levels. In vitro infection of primary human EC cultures and serum Ang2 proteins in scrub typhus patients support our animal studies, implying endothelial dysfunction in severe scrub typhus. Flow cytometric analyses of lung-recovered cells further revealed that pulmonary macrophages (MΦ) were polarized toward an M1-like phenotype (CD80+CD64+CD11b+Ly6G-) during the onset of disease and prior to host death, which correlated with the significant loss of CD31+CD45- ECs and M2-like (CD206+CD64+CD11b+Ly6G-) cells. In vitro studies indicated extensive bacterial replication in M2-type, but not M1-type, MΦs, implying the protective and pathogenic roles of M1-skewed responses. This is the first detailed investigation of lung cellular immune responses during acute O. tsutsugamushi infection. It uncovers specific biomarkers for vascular dysfunction and M1-skewed inflammatory responses, highlighting future therapeutic research for the control of this neglected tropical disease.
Identifiants
pubmed: 32119672
doi: 10.1371/journal.pntd.0007675
pii: PNTD-D-19-01266
pmc: PMC7067486
doi:
Substances chimiques
Angiopoietin-2
0
Receptor, TIE-2
EC 2.7.10.1
Tek protein, mouse
EC 2.7.10.1
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
e0007675Subventions
Organisme : NIAID NIH HHS
ID : R01 AI132674
Pays : United States
Organisme : NIAID NIH HHS
ID : T35 AI078878
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI060549
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI126343
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI117368
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
PLoS Negl Trop Dis. 2012 Jan;6(1):e1466
pubmed: 22253938
PLoS Negl Trop Dis. 2017 Jul 24;11(7):e0005765
pubmed: 28742087
PLoS One. 2015 Nov 25;10(11):e0143593
pubmed: 26606059
Genes Dev. 1994 Aug 15;8(16):1897-909
pubmed: 7958865
Am J Pathol. 1993 Jan;142(1):117-28
pubmed: 8424450
Blood. 2004 Jun 1;103(11):4150-6
pubmed: 14976056
Clin Exp Immunol. 2008 Jul;153(1):63-7
pubmed: 18505434
PLoS Negl Trop Dis. 2014 Aug 14;8(8):e3064
pubmed: 25122501
Microb Pathog. 2013 Feb;55:55-63
pubmed: 23088884
Am J Trop Med Hyg. 2007 Jun;76(6):1148-52
pubmed: 17556627
Emerg Infect Dis. 2006 Feb;12(2):256-62
pubmed: 16494751
PLoS Negl Trop Dis. 2014 Feb 06;8(2):e2648
pubmed: 24516677
J Infect. 2014 Nov;69(5):462-9
pubmed: 24995849
Infect Immun. 2006 Jul;74(7):4246-53
pubmed: 16790799
J Immunol. 1986 Aug 15;137(4):1270-4
pubmed: 3525675
Front Cell Infect Microbiol. 2016 Jul 29;6:80
pubmed: 27525249
PLoS One. 2016 Feb 04;11(2):e0148564
pubmed: 26844767
Science. 1997 Jul 4;277(5322):55-60
pubmed: 9204896
Mol Med. 2011 Mar-Apr;17(3-4):293-307
pubmed: 21046059
Int J Mol Sci. 2018 Jun 19;19(6):
pubmed: 29921749
Clin Microbiol Rev. 2018 Jan 31;31(2):
pubmed: 29386235
Nat Med. 2000 Apr;6(4):460-3
pubmed: 10742156
PLoS Negl Trop Dis. 2016 Sep 08;10(9):e0004991
pubmed: 27606708
Austin J Vasc Med. 2015 Jun 4;2(1):
pubmed: 26973981
J Inflamm (Lond). 2018 Jun 14;15:12
pubmed: 29946226
Infect Immun. 2000 Dec;68(12):6729-36
pubmed: 11083788
J Clin Invest. 2011 Jun;121(6):2278-89
pubmed: 21606590
PLoS Med. 2006 Mar;3(3):e46
pubmed: 16417407
Nat Med. 2006 Feb;12(2):235-9
pubmed: 16462802
PLoS One. 2012;7(6):e39042
pubmed: 22723924
Sci Rep. 2016 Oct 27;6:35950
pubmed: 27784899
Am J Trop Med Hyg. 2013 Aug;89(2):301-7
pubmed: 23926142
Front Immunol. 2018 Sep 04;9:2022
pubmed: 30233599
Int J Infect Dis. 2013 Nov;17(11):e981-7
pubmed: 23891643
Sci Transl Med. 2016 Sep 28;8(358):358ra128
pubmed: 27683553
Clin Microbiol Infect. 2010 May;16(5):447-51
pubmed: 19778303
Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):2472-7
pubmed: 26884170
Infect Immun. 2000 Feb;68(2):594-602
pubmed: 10639422
Crit Care Med. 2014 Oct;42(10):e654-62
pubmed: 25083983
PLoS Negl Trop Dis. 2016 Aug 01;10(8):e0004884
pubmed: 27479584
PLoS One. 2014 Jan 03;9(1):e82088
pubmed: 24404127
Am J Physiol Lung Cell Mol Physiol. 2016 May 1;310(9):L796-801
pubmed: 26944088
PLoS Negl Trop Dis. 2017 Mar 10;11(3):e0005453
pubmed: 28282373
J Immunol. 2018 Feb 15;200(4):1233-1240
pubmed: 29431689
Sci Rep. 2017 Aug 21;7(1):8965
pubmed: 28827726
Microb Pathog. 2010 Sep;49(3):95-104
pubmed: 20470879
J Am Soc Nephrol. 2017 Jul;28(7):1973-1982
pubmed: 28465380
Crit Care Med. 2007 Jan;35(1):199-206
pubmed: 17110873
Exp Appl Acarol. 2012 Sep;58(1):23-34
pubmed: 22527840
PLoS Negl Trop Dis. 2017 Dec 6;11(12):e0006127
pubmed: 29211737
PLoS Negl Trop Dis. 2014 Sep 25;8(9):e3191
pubmed: 25254971
PLoS One. 2013;8(2):e54841
pubmed: 23418431
PLoS Negl Trop Dis. 2014 Jul 10;8(7):e2966
pubmed: 25010338
Am J Respir Cell Mol Biol. 2013 Oct;49(4):503-10
pubmed: 23672262
Microb Pathog. 2017 Jun;107:335-340
pubmed: 28412201
J Vis Exp. 2013 Jun 23;(76):
pubmed: 23851980
Infect Immun. 1995 Sep;63(9):3253-8
pubmed: 7642253
Front Microbiol. 2019 Sep 06;10:2065
pubmed: 31555249
Infect Immun. 1994 Mar;62(3):1089-100
pubmed: 7509315
Trans R Soc Trop Med Hyg. 1976;70(5-6):444-8
pubmed: 402722
PLoS Negl Trop Dis. 2017 Mar 1;11(3):e0005408
pubmed: 28248956
Pathology. 2008 Apr;40(3):268-71
pubmed: 18428046
Am J Physiol Lung Cell Mol Physiol. 2014 Apr 15;306(8):L709-25
pubmed: 24508730
Am J Pathol. 2010 Dec;177(6):3233-43
pubmed: 20952594
Microbiol Immunol. 1999;43(8):751-7
pubmed: 10524792
PLoS Negl Trop Dis. 2016 Mar 04;10(3):e0004467
pubmed: 26943125
Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19615-20
pubmed: 24218580
PLoS One. 2013;8(1):e54570
pubmed: 23342173
Mod Pathol. 2001 Aug;14(8):752-9
pubmed: 11504834
Infect Immun. 2013 Feb;81(2):552-9
pubmed: 23230293
Tissue Barriers. 2015 Apr 03;3(1-2):e957508
pubmed: 25838975
PLoS Negl Trop Dis. 2011 May;5(5):e1028
pubmed: 21610853
Cytokine. 2011 Aug;55(2):251-9
pubmed: 21531574
Infect Immun. 2002 Sep;70(9):4841-50
pubmed: 12183528