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

Fiche publication

Date publication

mai 2023

Journal

The Journal of clinical investigation

Auteurs

Membres identifiés du Cancéropôle Est :
Dr SCHREIBER Valérie

Tous les auteurs :
Thirunavukkarasu S, Ahmed M, Rosa BA, Boothby M, Cho SH, Rangel-Moreno J, Mbandi SK, Schreiber V, Gupta A, Zúñiga J, Mitreva M, Kaushal D, Scriba TJ, Khader SA

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/37200107

Résumé

The ADP ribosyl transferases (PARPs 1-17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified based on their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). While PARP9 mRNA expression is significantly increased in progressive human tuberculosis (TB), its participation in host immunity to TB is unknown. Here, we show that PARP9 mRNA encoding the MARylating PARP9 enzyme is upregulated during TB in humans and mice and provide evidence of a critical modulatory role for PARP9 in DNA damage, cGAS and type I IFN production during TB. Thus, Parp9-deficient mice are susceptible to Mtb infection and exhibit increased TB disease, cGAS expression, cGAMP and type I IFN production along with upregulation of complement and coagulation pathways. Enhanced Mtb susceptibility is type I IFN-dependent, as blockade of IFNAR signaling reversed the enhanced susceptibility of Parp9-/- mice. Thus, in sharp contrast with 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.