Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality

被引：10

作者：

Albert, Marie-Christine ^{[1
,2
]}

Uranga-Murillo, Iratxe ^{[3
,4
,5
]}

Arias, Maykel ^{[3
,4
,5
]}

De Miguel, Diego ^{[4
]}

Pena, Natacha ^{[4
]}

Montinaro, Antonella ^{[6
]}

Varanda, Ana Beatriz ^{[1
,2
]}

Theobald, Sebastian J. ^{[7
,8
,9
,10
,11
]}

Areso, Itziar ^{[6
]}

Saggau, Julia ^{[1
,2
,12
,13
]}

Koch, Manuel ^{[14
,15
]}

Liccardi, Gianmaria ^{[12
,13
]}

Peltzer, Nieves ^{[1
,9
,10
,16
]}

Rybniker, Jan ^{[7
,8
,9
,10
,11
]}

Hurtado-Guerrero, Ramon ^{[17
,18
,19
]}

Merino, Pedro ^{[17
]}

Monzon, Marta ^{[20
,21
]}

Badiola, Juan J. ^{[20
]}

Reindl-Schwaighofer, Roman ^{[22
]}

Sanz-Pamplona, Rebeca ^{[4
,19
,23
]}

Cebollada-Solanas, Alberto ^{[24
]}

Megyesfalvi, Zsolt ^{[25
,26
,27
,28
]}

Dome, Balazs ^{[25
,26
,27
,28
,29
]}

Secrier, Maria ^{[30
]}

Hartmann, Boris ^{[31
]}

Bergmann, Michael ^{[32
]}

Pardo, Julian ^{[3
,4
,5
]}

Walczak, Henning ^{[1
,2
,6
]}

机构：

[1] Univ Cologne, Cell Death Inflammat & Immun Lab, CECAD Cluster Excellence, D-50931 Cologne, Germany

[2] Univ Cologne, Inst Biochem 1, Fac Med, Ctr Biochem,Cell Death Inflammat & Immun Lab, D-50931 Cologne, Germany

[3] Inst Salud Carlos III, CIBER Enfermedades Infecciosas, Madrid 28029, Spain

[4] Aragon Hlth Res Inst IIS Aragon, San Juan Bosco 13, Zaragoza 50009, Spain

[5] Univ Zaragoza, Dept Microbiol Paediat Radiol & Prevent Med & Publ, Zaragoza 50009, Spain

[6] UCL, UCL Canc Inst, Ctr Cell Death Canc & Inflammat CCCI, London WC1E 6DD, England

[7] Univ Cologne, Dept Internal Med 1, Fac Med, D-50931 Cologne, Germany

[8] Univ Cologne, Univ Hosp Cologne, D-50931 Cologne, Germany

[9] Univ Cologne, Fac Med, D-50931 Cologne, Germany

[10] Univ Cologne, Univ Hosp Cologne, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany

[11] German Ctr Infect Res DZIF, Partner Site Bonn Cologne, D-50931 Cologne, Germany

[12] Univ Cologne, Inst Biochem 1, Fac Med, Ctr Biochem,Genome Instabil Inflammat & Cell Death, D-50931 Cologne, Germany

[13] Univ Cologne, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany

[14] Univ Cologne, Inst Dent Res & Oral Musculoskeletal Biol, Fac Med, D-50931 Cologne, Germany

[15] Univ Hosp Cologne, D-50931 Cologne, Germany

[16] Univ Cologne, Dept Translat Genom, D-50931 Cologne, Germany

[17] Univ Zaragoza, Inst Biocomp & Fis Sistemas Complejos BIFI, Zaragoza 50018, Spain

[18] Univ Copenhagen, Copenhagen Ctr Glyc, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark

[19] Fdn ARAID, Zaragoza 50018, Spain

[20] Univ Zaragoza, Inst Hlth Res Aragon IIS, Res Ctr Encephalopathies & Transmissible Emerging, Zaragoza 50013, Spain

[21] Univ Zaragoza, Dept Human Anat & Histol, Zaragoza 50009, Spain

[22] Med Univ Vienna, Dept Med 3, A-1090 Vienna, Austria

[23] Inst Salud Carlos III, CIBER Epidemiol & Salud Publ, Madrid 28029, Spain

[24] Inst Aragones Ciencias Salud IACS, Aragon Biomed Res Ctr CIBA, Unidad Biocomp, Zaragoza 50018, Spain

[25] Med Univ Vienna, Dept Thorac Surg, A-1090 Vienna, Austria

[26] Semmelweis Univ, Dept Thorac Surg, H-1122 Budapest, Hungary

[27] Natl Inst Oncol, H-1122 Budapest, Hungary

[28] Natl Koranyi Inst Pulmonol, H-1121 Budapest, Hungary

[29] Lund Univ, Dept Translat Med, SE-22100 Lund, Sweden

[30] UCL, UCL Genet Inst, Dept Genet Evolut & Environm, London WC1E 6BT, England

[31] Inst Vet Dis Control AGES, Virol Grp, A-2340 Modling, Austria

[32] Med Univ Vienna, Comprehens Canc Ctr, Dept Gen Surg, Div Visceral Surg, A-1090 Vienna, Austria

来源：

CELL DEATH AND DIFFERENTIATION | 2024年 / 31卷 / 05期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

ACUTE LUNG INJURY; INFLAMMATION; SARS-COV-2; PNEUMONIA; INNATE; LIGAND;

D O I：

10.1038/s41418-024-01278-6

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19. Concomitantly with occurrence of cell death and inflammation, FasL expression was significantly increased on inflammatory monocytic macrophages and NK cells in the lungs of MA20-infected mice. Importantly, therapeutic FasL inhibition markedly increased survival of both, young and old MA20-infected mice coincident with substantially reduced cell death and inflammation in their lungs. Intriguingly, FasL was also increased in the bronchoalveolar lavage fluid of critically-ill COVID-19 patients. Together, these results identify FasL as a crucial host factor driving the immuno-pathology that underlies COVID-19 severity and lethality, and imply that patients with severe COVID-19 may significantly benefit from therapeutic inhibition of FasL.

引用

页码：544 / 557

页数：14

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