Frontiers in Immunology (Nov 2020)
GPR183 Regulates Interferons, Autophagy, and Bacterial Growth During Mycobacterium tuberculosis Infection and Is Associated With TB Disease Severity
- Stacey Bartlett,
- Adrian Tandhyka Gemiarto,
- Minh Dao Ngo,
- Haressh Sajiir,
- Semira Hailu,
- Roma Sinha,
- Cheng Xiang Foo,
- Léanie Kleynhans,
- Happy Tshivhula,
- Tariq Webber,
- Helle Bielefeldt-Ohmann,
- Helle Bielefeldt-Ohmann,
- Nicholas P. West,
- Nicholas P. West,
- Andriette M. Hiemstra,
- Candice E. MacDonald,
- Liv von Voss Christensen,
- Larry S. Schlesinger,
- Gerhard Walzl,
- Mette Marie Rosenkilde,
- Thomas Mandrup-Poulsen,
- Katharina Ronacher,
- Katharina Ronacher,
- Katharina Ronacher
Affiliations
- Stacey Bartlett
- Translational Research Institute–Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
- Adrian Tandhyka Gemiarto
- Translational Research Institute–Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
- Minh Dao Ngo
- Translational Research Institute–Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
- Haressh Sajiir
- Translational Research Institute–Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
- Semira Hailu
- Translational Research Institute–Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
- Roma Sinha
- Translational Research Institute–Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
- Cheng Xiang Foo
- Translational Research Institute–Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
- Léanie Kleynhans
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Happy Tshivhula
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Tariq Webber
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Helle Bielefeldt-Ohmann
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
- Helle Bielefeldt-Ohmann
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
- Nicholas P. West
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
- Nicholas P. West
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
- Andriette M. Hiemstra
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Candice E. MacDonald
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Liv von Voss Christensen
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Larry S. Schlesinger
- Host-Pathogens Interactions Program, Texas Biomedical Research Institute, San Antonio, TX, United States
- Gerhard Walzl
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Mette Marie Rosenkilde
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Thomas Mandrup-Poulsen
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Katharina Ronacher
- Translational Research Institute–Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
- Katharina Ronacher
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Katharina Ronacher
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
- DOI
- https://doi.org/10.3389/fimmu.2020.601534
- Journal volume & issue
-
Vol. 11
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.
Keywords
