Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase

Area of Science:

• Immunology
• Microbiology
• Biochemistry

Background:

• Mycobacterium tuberculosis infection triggers host cytosolic surveillance pathways (CSP) via cyclic dinucleotides (CDNs), leading to type I interferon (IFN) expression.
• This innate immune response is crucial for controlling bacterial infections but can be subverted by pathogens.

Purpose of the Study:

• To investigate the mechanism by which Mycobacterium tuberculosis evades the host's type I IFN response.
• To identify bacterial factors involved in subverting the cytosolic surveillance pathway (CSP).

Main Methods:

• Enzyme activity assays to measure hydrolysis of c-di-AMP and cGAMP by CdnP.
• Genetic manipulation of Mycobacterium tuberculosis (mutation of cdnP) to assess virulence.
• Testing the efficacy of FDA-approved phosphodiesterase (PDE) inhibitors and dinucleotide mimetics against CdnP.

Main Results:

• Mycobacterium tuberculosis possesses a phosphodiesterase (PDE) enzyme, CdnP, that degrades both bacterial c-di-AMP and host cGAMP.
• Loss of CdnP function or host ENPP1 attenuates bacterial virulence, indicating their importance in infection.
• CdnP is effectively inhibited by specific PDE inhibitors and dinucleotide mimetics.

Conclusions:

• Mycobacterium tuberculosis subverts host immunity by hydrolyzing key signaling molecules (CDNs) through its PDE, CdnP.
• CDN homeostasis is critical for controlling M. tuberculosis infection.
• Bacterial PDE CdnP represents a potential novel antimicrobial target for tuberculosis treatment.