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Published on: January 24, 2016
Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating
Shyamala Thirunavukkarasu1, Mushtaq Ahmed1, Bruce A Rosa2,3
1Department of Molecular Microbiology.
Abstract:
The ADP ribosyltransferases (PARPs 1-17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified on the basis of their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). Although PARP9 mRNA expression is significantly increased in progressive tuberculosis (TB) in humans, its participation in host immunity to TB is unknown. Here, we show that PARP9 mRNA encoding the MARylating PARP9 enzyme was upregulated during TB in humans and mice and provide evidence of a critical modulatory role for PARP9 in DNA damage, cyclic GMP-AMP synthase (cGAS) expression, and type I IFN production during TB. Thus, Parp9-deficient mice were susceptible to Mycobacterium tuberculosis infection and exhibited increased TB disease, cGAS and 2'3'-cyclic GMP-AMP (cGAMP) expression, and type I IFN production, along with upregulation of complement and coagulation pathways. Enhanced M. tuberculosis susceptibility is type I IFN dependent, as blockade of IFN α receptor (IFNAR) signaling reversed the enhanced susceptibility of Parp9-/- mice. Thus, in sharp contrast to PARP9 enhancement of type I IFN production in viral infections, this member of the MAR family plays a protective role by limiting type I IFN responses during TB.
Insights
Poly(ADP-ribose) polymerase 9 (PARP9) is upregulated in tuberculosis (TB). PARP9 limits type I interferon responses, playing a protective role against Mycobacterium tuberculosis infection.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- ADP ribosyltransferases (PARPs) are crucial for DNA repair and cellular processes.
- PARP9, a mono-ADP-ribosylating enzyme, shows increased mRNA in human tuberculosis (TB).
- The role of PARP9 in host immunity against TB remains largely unexplored.
Purpose of the Study:
- To investigate the role of PARP9 in host immune responses during tuberculosis.
- To elucidate PARP9's function in DNA damage, cGAS-STING pathway activation, and type I interferon production in TB.
Main Methods:
- Analysis of PARP9 mRNA expression in human and murine TB models.
- Phenotypic characterization of Parp9-deficient mice infected with Mycobacterium tuberculosis.
- Assessment of DNA damage, cGAS and cGAMP levels, type I interferon production, and complement/coagulation pathways.
- Intervention studies using IFNAR signaling blockade.
Main Results:
- PARP9 mRNA is upregulated in TB patients and mouse models.
- Parp9-deficient mice exhibit increased susceptibility to M. tuberculosis infection and TB disease.
- PARP9 deficiency leads to elevated cGAS and cGAMP expression and heightened type I interferon production.
- Enhanced susceptibility in Parp9-/- mice is dependent on type I interferon signaling.
Conclusions:
- PARP9 plays a critical role in modulating DNA damage, cGAS expression, and type I interferon responses during TB.
- PARP9 acts protectively in TB by limiting type I interferon responses, contrasting its role in viral infections.
- Targeting PARP9 could offer novel therapeutic strategies for managing tuberculosis.
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