Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production
Shyamala Thirunavukkarasu, … , Thomas J. Scriba, Shabaana A. Khader
Shyamala Thirunavukkarasu, … , Thomas J. Scriba, Shabaana A. Khader
Published May 18, 2023
Citation Information: J Clin Invest. 2023;133(12):e158630. https://doi.org/10.1172/JCI158630.
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Research Article Immunology Infectious disease

Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production

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.

Authors

Shyamala Thirunavukkarasu, Mushtaq Ahmed, Bruce A. Rosa, Mark Boothby, Sung Hoon Cho, Javier Rangel-Moreno, Stanley K. Mbandi, Valérie Schreiber, Ananya Gupta, Joaquin Zuniga, Makedonka Mitreva, Deepak Kaushal, Thomas J. Scriba, Shabaana A. Khader

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Figure 7

Enhanced DNA damage in Parp9–/– mice is type I IFN mediated.

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Enhanced DNA damage in Parp9–/– mice is type I IFN mediated. B6 and Parp...
B6 and Parp9–/– mice were infected with M. tuberculosis HN878 (100 CFU) by the aerosol route. Mouse α-IFNAR or the mouse IgG1 isotype control antibody, at 500 μg/kg BW on days 7–9 and 250 μg/kg BW on alternate days, was administered i.p. in 300 μL PBS/mice until 30 dpi. (A) Representative images and corresponding dot plot of lung sections from M. tuberculosis HN878–infected B6 and Parp9–/– mice treated with α-IFNAR or an isotype control antibody. Lung sections were stained with α-pH2Ax antibody to assess DNA damage. The percentage of pH2Ax+ cells per high-powered field was quantitated manually. Scale bars: 100 μm. Original magnification, ×200. (B) Bacterial CFU in the in vitro–cultured M. tuberculosis HN878–infected BMDMs with or without α-IFNAR treatment. Data points represent the mean ± SEM, and analysis was done using 1-way ANOVA with Tukey’s multiple-comparison test (n = 3–5 mice per group). P ≤ 0.05 was considered significant.