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GPR183 Regulates Interferons, Autophagy, and Bacterial Growth During Mycobacterium tuberculosis Infection and Is

Stacey Bartlett1, Adrian Tandhyka Gemiarto1, Minh Dao Ngo1

  • 1Translational Research Institute-Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia.

Frontiers in Immunology
|November 26, 2020
PubMed

Insights

The oxysterol receptor GPR183 plays a key role in controlling mycobacterial infections. Activating GPR183 inhibits the growth of Mycobacterium tuberculosis, offering a potential therapeutic target for tuberculosis.

Area of Science:

  • Immunology
  • Infectious Diseases
  • Molecular Biology

Background:

  • Oxidized cholesterols (oxysterols) are crucial immune signaling molecules.
  • The role of oxysterols in mycobacterial infections, particularly tuberculosis (TB), remains largely unexplored.

Purpose of the Study:

  • To investigate the role of the oxysterol receptor GPR183 in mycobacterial infections.
  • To determine the impact of GPR183 on the growth of Mycobacterium tuberculosis (Mtb) and host immune responses.

Main Methods:

  • Quantified GPR183 expression in patients with TB and type 2 diabetes (T2D).
  • Assessed the effect of GPR183 activation (using 7α,25-dihydroxycholesterol) and antagonism on Mtb and Mycobacterium bovis BCG growth in human monocytes.
  • Analyzed cytokine expression (IFN-β, IL-10) and autophagy.
  • Studied Mtb infection in GPR183-deficient mice.

Main Results:

  • Reduced GPR183 expression was observed in patients with TB and T2D, correlating with TB severity.
  • GPR183 activation inhibited Mtb and BCG growth in human monocytes, an effect blocked by a GPR183 antagonist.
  • Inhibition of mycobacterial growth was linked to decreased IFN-β and IL-10 and enhanced autophagy.
  • GPR183-deficient mice exhibited increased lung Mtb burden and disrupted interferon responses during early infection.

Conclusions:

  • GPR183 is a critical regulator of intracellular mycobacterial growth.
  • GPR183 influences host interferon responses during mycobacterial infection.
  • Targeting GPR183 may represent a novel therapeutic strategy for managing mycobacterial infections.
Keywords:
7α,25-dihydroxycholesterolEBI2GPR183Mycobacterium tuberculosisautophagydiabeteshost-direct therapiesoxysterols

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