Aberrant type 1 immunity drives susceptibility to mucosal fungal infections

被引：102

作者：

Break, Timothy J. ^{[1
]}

Oikonomou, Vasileios ^{[1
]}

Dutzan, Nicolas ^{[2
]}

Desai, Jigar, V ^{[1
]}

Swidergall, Marc ^{[3
,4
]}

Freiwald, Tilo ^{[5
]}

Chauss, Daniel ^{[5
]}

Harrison, Oliver J. ^{[6
,21
]}

Alejo, Julie ^{[7
]}

Williams, Drake W. ^{[2
]}

Pittaluga, Stefania ^{[7
]}

Lee, Chyi-Chia R. ^{[7
]}

Bouladoux, Nicolas ^{[6
]}

Swamydas, Muthulekha ^{[1
]}

Hoffman, Kevin W. ^{[8
]}

Greenwell-Wild, Teresa ^{[2
]}

Bruno, Vincent M. ^{[9
]}

Rosen, Lindsey B. ^{[10
]}

Lwin, Wint ^{[11
]}

Renteria, Andy ^{[1
]}

Pontejo, Sergio M. ^{[12
]}

Shannon, John P. ^{[13
]}

Myles, Ian A. ^{[14
]}

Olbrich, Peter ^{[10
]}

Ferre, Elise M. N. ^{[1
]}

Schmitt, Monica ^{[1
]}

Martin, Daniel ^{[15
]}

Barber, Daniel L. ^{[17
]}

Solis, Norma, V ^{[3
]}

Notarangelo, Luigi D. ^{[18
]}

Serreze, David, V ^{[19
]}

Matsumoto, Mitsuru ^{[20
]}

Hickman, Heather D. ^{[13
]}

Murphy, Philip M. ^{[12
]}

Anderson, Mark S. ^{[1
]}

Lim, Jean K. ^{[8
]}

Holland, Steven M. ^{[10
]}

Filler, Scott G. ^{[3
,4
]}

Afzali, Behdad ^{[5
]}

Belkaid, Yasmine ^{[6
]}

Moutsopoulos, Niki M. ^{[2
]}

Lionakis, Michail S. ^{[1
]}

机构：

[1] NIAID, Fungal Pathogenesis Sect, Lab Clin Immunol & Microbiol LCIM, 9000 Rockville Pike, Bethesda, MD 20892 USA

[2] Natl Inst Dent & Craniofacial Res NIDCR, Oral Immun & Inflammat Sect, Bethesda, MD USA

[3] Harbor UCLA Med Ctr, Lundquist Inst Biomed Innovat, Torrance, CA 90509 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[5] NIDDK, Immunoregulat Sect, Kidney Dis Branch, Bethesda, MD USA

[6] NIAID, Metaorganism Immun Sect, Lab Immune Syst Biol, 9000 Rockville Pike, Bethesda, MD 20892 USA

[7] NCI, Lab Pathol, Ctr Canc Res, Bethesda, MD 20892 USA

[8] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA

[9] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA

[10] NIAID, Immunopathogenesis Sect, LCIM, 9000 Rockville Pike, Bethesda, MD 20892 USA

[11] Univ Calif San Francisco, Diabet Ctr, San Francisco, CA 94143 USA

[12] NIAID, Mol Signaling Sect, Lab Mol Immunol, 9000 Rockville Pike, Bethesda, MD 20892 USA

[13] NIAID, Viral Immun & Pathogenesis Unit, LCIM, 9000 Rockville Pike, Bethesda, MD 20892 USA

[14] NIAID, Epithelial Therapeut Unit, LCIM, 9000 Rockville Pike, Bethesda, MD 20892 USA

[15] NIDCR, Genom & Computat Biol Core, Bethesda, MD USA

[16] Natl Inst Deafness & Other Commun Disorders NIDCD, Genom & Computat Biol Core, Bethesda, MD USA

[17] NIAID, T Lymphocyte Biol Sect, Lab Parasit Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA

[18] NIAID, Immune Deficiency Genet Sect, LCIM, 9000 Rockville Pike, Bethesda, MD 20892 USA

[19] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA

[20] Tokushima Univ, Inst Enzyme Res, Div Mol Immunol, Tokushima, Japan

[21] Benaroya Res Inst Virginia Mason, 1201 Ninth Avenge, Seattle, WA 98101 USA

来源：

SCIENCE | 2021年 / 371卷 / 6526期

关键词：

CHRONIC MUCOCUTANEOUS CANDIDIASIS; STAT1; MUTATIONS; AIRE; CELLS; MICE; BACTERIAL; MODEL; AUTOIMMUNITY; RUXOLITINIB; MECHANISMS;

D O I：

10.1126/science.aay5731

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-gamma (IFN-gamma)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-gamma or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.

引用

页码：252 / +

页数：76

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