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Mycobacterial CpsA activates type I IFN signaling in macrophages via cGAS-mediated pathway

Yue Ding1, Jingfeng Tong1, Geyang Luo1

  • 1Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.

Iscience
|May 20, 2024
PubMed

Insights

Mycobacterium tuberculosis protein CpsA is essential for initiating type I interferon (IFN) production during infection. CpsA deficiency impairs IFN expression by affecting the cGAS-TBK1-IRF3 pathway and phagosomal integrity.

Area of Science:

  • Immunology
  • Microbiology
  • Pathogenesis

Background:

  • Type I interferon (IFN) production is critical in tuberculosis (TB) pathogenesis.
  • The bacterial factors triggering IFN production in TB are not fully understood.
  • CpsA, a protein from Mycobacterium species, is known for virulence and inhibiting host cell processes.

Purpose of the Study:

  • To investigate the role of CpsA in initiating type I IFN production during mycobacterial infections.
  • To elucidate the molecular mechanisms by which CpsA influences IFN expression.

Main Methods:

  • Utilized CpsA full deletion mutant studies in *Mycobacterium marinum* and *Mycobacterium tuberculosis*.
  • Assessed IFN production in infected macrophages *in vitro* and in zebrafish and mice *in vivo*.
  • Analyzed the cGAS-TBK1-IRF3 pathway, TBK1/IRF3 phosphorylation, and cytosolic DNA levels.

Main Results:

  • CpsA deficiency significantly reduced type I IFN production in infected macrophages, zebrafish, and mice.
  • CpsA-deficient strains showed decreased phosphorylation of TBK1 and IRF3, indicating impaired cGAS-TBK1-IRF3 pathway activation.
  • CpsA deficiency led to lower cytosolic DNA levels and impaired phagosomal membrane rupture.

Conclusions:

  • Mycobacterial CpsA plays a novel and essential role in inducing type I IFN production.
  • CpsA influences type I IFN expression via the cGAS-TBK1-IRF3 pathway and by affecting phagosomal integrity.
  • These findings provide new insights into the mechanisms of mycobacterial pathogenesis and host immune response.
Keywords:
ImmunologyMicrobiologyMolecular microbiology

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