Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization.
Animals
Cytokines
/ genetics
Intercellular Signaling Peptides and Proteins
/ genetics
Macrophages, Alveolar
/ immunology
Male
Mice
Mice, Knockout
Pneumonia, Pneumococcal
/ genetics
Proto-Oncogene Proteins
/ genetics
Receptor Protein-Tyrosine Kinases
/ genetics
Respiratory Syncytial Virus Infections
/ genetics
Respiratory Syncytial Viruses
/ immunology
Axl Receptor Tyrosine Kinase
Cytokines
Immunology
Infectious disease
Innate immunity
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
11
10
2018
accepted:
26
02
2020
pubmed:
5
5
2020
medline:
3
2
2021
entrez:
5
5
2020
Statut:
ppublish
Résumé
Patients with respiratory syncytial virus (RSV) infection exhibit enhanced susceptibility to subsequent pneumococcal infections. However, the underlying mechanisms involved in this increased susceptibility remain unclear. Here, we identified potentially novel cellular and molecular cascades triggered by RSV infection to exacerbate secondary pneumococcal pneumonia. RSV infection stimulated the local production of growth arrest-specific 6 (Gas6). The Gas6 receptor Axl was crucial for attenuating pneumococcal immunity in that the Gas6/Axl blockade fully restored antibacterial immunity. Mechanistically, Gas6/Axl interaction regulated the conversion of alveolar macrophages from an antibacterial phenotype to an M2-like phenotype that did not exhibit antibacterial activity, and the attenuation of caspase-1 activation and IL-18 production in response to pneumococcal infection. The attenuated IL-18 production failed to drive both NK cell-mediated IFN-γ production and local NO and TNF-α production, which impair the control of bacterial infection. Hence, the RSV-mediated Gas6/Axl activity attenuates the macrophage-mediated protection against pneumococcal infection. The Gas6/Axl axis could be a potentially novel therapeutic target for RSV-associated secondary bacterial infection.
Identifiants
pubmed: 32364537
pii: 125505
doi: 10.1172/JCI125505
pmc: PMC7260035
doi:
pii:
Substances chimiques
Cytokines
0
Intercellular Signaling Peptides and Proteins
0
Proto-Oncogene Proteins
0
growth arrest-specific protein 6
0
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Axl Receptor Tyrosine Kinase
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3021-3037Références
N Engl J Med. 1982 Jun 10;306(23):1377-83
pubmed: 6281639
Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16513-16518
pubmed: 31363052
Ann Am Thorac Soc. 2014 Dec;11 Suppl 5:S303-5
pubmed: 25525737
J Exp Med. 2017 Aug 7;214(8):2387-2404
pubmed: 28694385
Mucosal Immunol. 2010 May;3(3):291-300
pubmed: 20404812
Am J Respir Cell Mol Biol. 2008 Nov;39(5):522-9
pubmed: 18483419
N Engl J Med. 2005 Apr 28;352(17):1749-59
pubmed: 15858184
J Infect Chemother. 2011 Feb;17(1):87-90
pubmed: 20700753
Nat Med. 2008 May;14(5):558-64
pubmed: 18438414
J Med Virol. 2006 Jun;78(6):829-38
pubmed: 16628585
Proc Natl Acad Sci U S A. 1985 Nov;82(21):7404-8
pubmed: 3933006
J Pediatr. 1992 Jun;120(6):856-62
pubmed: 1534364
PLoS Pathog. 2015 Jun 17;11(6):e1004978
pubmed: 26083387
Nat Microbiol. 2019 Aug;4(8):1328-1336
pubmed: 31110359
Pediatrics. 2010 Dec;126(6):e1453-60
pubmed: 21098154
J Clin Invest. 2011 Sep;121(9):3657-65
pubmed: 21841308
Am J Respir Cell Mol Biol. 2014 Nov;51(5):615-25
pubmed: 24810144
Autophagy. 2016 Dec;12(12):2326-2343
pubmed: 27780404
J Allergy Clin Immunol. 2016 Sep;138(3):814-824.e11
pubmed: 27156176
Immunol Cell Biol. 2017 Nov;95(10):906-915
pubmed: 28722020
J Infect. 2015 Oct;71(4):458-69
pubmed: 26149186
Thorax. 2006 Jul;61(7):611-5
pubmed: 16537670
Nature. 2016 Apr 14;532(7598):240-244
pubmed: 27049947
Nat Immunol. 2018 Dec;19(12):1299-1308
pubmed: 30374129
Cancer Res. 2010 Feb 15;70(4):1544-54
pubmed: 20145120
Am J Respir Crit Care Med. 2014 Jul 15;190(2):196-207
pubmed: 24941423
Am J Respir Cell Mol Biol. 2015 Mar;52(3):349-64
pubmed: 25100610
Pediatr Res. 1983 Sep;17(9):753-8
pubmed: 6622111
J Biol Chem. 1996 Nov 22;271(47):30022-7
pubmed: 8939948
J Exp Med. 2008 Feb 18;205(2):323-9
pubmed: 18227219
J Immunol. 2014 Oct 1;193(7):3559-65
pubmed: 25156363
J Exp Med. 2006 Aug 7;203(8):1891-901
pubmed: 16831897
Mucosal Immunol. 2017 Mar;10(2):460-469
pubmed: 27220813
Lancet. 2017 Sep 2;390(10098):946-958
pubmed: 28689664
J Clin Invest. 2009 Jul;119(7):1910-20
pubmed: 19487810
Biochem J. 2005 May 1;387(Pt 3):727-35
pubmed: 15579134
PLoS Med. 2015 Jan 06;12(1):e1001776
pubmed: 25562317
Blood. 2014 Apr 17;123(16):2460-9
pubmed: 24596417
J Immunol. 2014 Apr 15;192(8):3569-81
pubmed: 24659691
Cell. 2007 Dec 14;131(6):1124-36
pubmed: 18083102
PLoS Pathog. 2015 Oct 16;11(10):e1005217
pubmed: 26473724
J Exp Med. 1993 Dec 1;178(6):2243-7
pubmed: 8245795
Lancet. 2010 May 1;375(9725):1545-55
pubmed: 20399493
Oncogene. 1997 May 1;14(17):2033-9
pubmed: 9160883
Am J Respir Crit Care Med. 2011 May 15;183(10):1391-401
pubmed: 21169470
Arch Dis Child. 2004 Dec;89(12):1155-7
pubmed: 15557055
J Virol. 2008 Apr;82(7):3236-49
pubmed: 18216092
Infect Drug Resist. 2011;4:221-4
pubmed: 22259251
Nat Immunol. 2001 Aug;2(8):732-8
pubmed: 11477410
Front Immunol. 2014 Nov 28;5:614
pubmed: 25506346