GPR183 Regulates Interferons, Autophagy, and Bacterial Growth During Mycobacterium tuberculosis Infection and Is Associated With TB Disease Severity

被引：29

作者：

Bartlett, Stacey ^{[1
]}

Gemiarto, Adrian Tandhyka ^{[1
]}

Ngo, Minh Dao ^{[1
]}

Sajiir, Haressh ^{[1
]}

Hailu, Semira ^{[1
]}

Sinha, Roma ^{[1
]}

Foo, Cheng Xiang ^{[1
]}

Kleynhans, Leanie ^{[2
]}

Tshivhula, Happy ^{[2
]}

Webber, Tariq ^{[2
]}

Bielefeldt-Ohmann, Helle ^{[3
,4
]}

West, Nicholas P. ^{[3
,4
]}

Hiemstra, Andriette M. ^{[2
]}

MacDonald, Candice E. ^{[2
]}

Christensen, Liv von Voss ^{[5
]}

Schlesinger, Larry S. ^{[6
]}

Walzl, Gerhard ^{[2
]}

Rosenkilde, Mette Marie ^{[5
]}

Mandrup-Poulsen, Thomas ^{[5
]}

Ronacher, Katharina ^{[1
,2
,4
]}

机构：

[1] Univ Queensland, Mater Res Inst, Translat Res Inst, Brisbane, Qld, Australia

[2] Stellenbosch Univ, DSI NRF Ctr Excellence Biomed TB Res, South African Med Res Council Ctr TB Res, Div Mol Biol & Human Genet,Fac Med & Hlth Sci, Cape Town, South Africa

[3] Univ Queensland, Sch Chem & Mol Biosci, St Lucia, Qld, Australia

[4] Univ Queensland, Australian Infect Dis Res Ctr, Brisbane, Qld, Australia

[5] Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark

[6] Texas Biomed Res Inst, Host Pathogens Interact Program, San Antonio, TX USA

来源：

FRONTIERS IN IMMUNOLOGY | 2020年 / 11卷

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

Mycobacterium tuberculosis; diabetes; oxysterols; 7; alpha; 25-dihydroxycholesterol; GPR183; EBI2; host-direct therapies; autophagy; RECEPTOR EBI2; 7-TRANSMEMBRANE RECEPTOR; CONVERGING EPIDEMICS; IL-1-BETA PRODUCTION; RESEARCH AGENDA; I INTERFERONS; OXYSTEROLS; MIGRATION; IDENTIFICATION; MACROPHAGES;

D O I：

10.3389/fimmu.2020.601534

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Oxidized cholesterols have emerged as important signaling molecules of immune function, but little is known about the role of these oxysterols during mycobacterial infections. We found that expression of the oxysterol-receptor GPR183 was reduced in blood from patients with tuberculosis (TB) and type 2 diabetes (T2D) compared to TB patients without T2D and was associated with TB disease severity on chest x-ray. GPR183 activation by 7 alpha,25-dihydroxycholesterol (7 alpha,25-OHC) reduced growth of Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis BCG in primary human monocytes, an effect abrogated by the GPR183 antagonist GSK682753. Growth inhibition was associated with reduced IFN-beta and IL-10 expression and enhanced autophagy. Mice lacking GPR183 had significantly increased lung Mtb burden and dysregulated IFNs during early infection. Together, our data demonstrate that GPR183 is an important regulator of intracellular mycobacterial growth and interferons during mycobacterial infection.

引用

页数：11

共 42 条

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