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

Stacey Bartlett,Larry S Schlesinger,Gerhard Walzl,Roma Sinha,Minh Dao Ngo,Katharina Ronacher,Léanie Kleynhans,Liv Von Voss Christensen,Haressh Sajiir,Cheng Xiang Foo,Adrian Tandhyka Gemiarto,Happy Tshivhula,Tariq Webber,Nicholas P West,Semira Hailu,Candice Macdonald ,Helle Bielefeldt‐Ohmann ,Andriëtte Hiemstra ,Thomas Mandrup‐Poulsen ,Mette M Rosenkilde

doi:10.3389/fimmu.2020.601534

Abstract

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 7α,25-dihydroxycholesterol (7α,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-β 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.

Highlights

Patients with tuberculosis and type 2 diabetes (TB–T2D) comorbidity have increased bacterial burden and more severe disease, characterized by higher sputum smear grading scores and greater lung involvement on chest x-ray compared to TB patients without T2D [1, 2]
Among genes differentially expressed between TB and TB + T2D we identified a single G protein-coupled receptor (GPCR), GPR183
GPR183 expression was significantly down-regulated at diagnosis (p = 0.03, t-test) in blood from TB + T2D patients compared to TB patients without T2D (Figure 1A)

Summary

Introduction

Patients with tuberculosis and type 2 diabetes (TB–T2D) comorbidity have increased bacterial burden and more severe disease, characterized by higher sputum smear grading scores and greater lung involvement on chest x-ray compared to TB patients without T2D [1, 2]. The reason for the increased disease severity has largely been attributed to hyperglycemiamediated immune dysfunction, but hyperglycemia alone does not fully explain these observations [3, 4]. We show here that GPR183 is a key regulator of intracellular bacterial growth and type-I IFN production during mycobacterial infection and reduced GPR183 expression is associated with increased TB disease severity

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