Tuberculosis (TB), a devastating pulmonary disease caused by the bacillus Mycobacterium tuberculosis (Mtb), is a global public health thread that results in over 10 million new cases and nearly 2 million deaths a year. Even though most cases can be cured by standard TB therapy, increasing drug-resistance calls for the development of new and improved treatment options. Since most individuals are able to contain Mtb infection without developing TB, a better understanding of the immune response to Mtb may identify targets for host-directed therapies that could improve the treatment of TB. Pyrazinamide (PZA) has been a fundamental component of standard TB therapy for decades but its mechanism of action remains poorly defined. In contrast to other TB drugs, PZA has host-directed as well as antimicrobial activity and stunts pro-inflammatory cytokine responses to Mtb in a pattern that suggests suppression of the NF-?B signaling pathway. However, a mammalian target of PZA has not yet been identified. I recently demonstrated that PZA inhibits the host enzyme Poly(ADP-ribose) Polymerase-1 (PARP-1), a key immune regulator required for tumor necrosis factor alpha (TNF-?) production and NF-?B target gene expression. Although the role of PARP-1 in TB infection has not yet been determined, PARP-1 is potently activated by conditions induced in Mtb infection and thus may be an important driver of TB immune responses and pathogenesis. Therefore, PARP-1 inhibition may be the mechanism behind PZA?s immunomodulatory activity and a potential host-directed intervention that may improve the treatment of TB. In this study, I propose to validate PARP-1 as a key host target of PZA and evaluate PARP-1 inhibition in TB therapy. I will first systematically characterize the role of PARP-1 in a mouse model of TB infection by comparing the susceptibility, disease progression and immune responses to Mtb in wild type (WT) and PARP-1 knock-out (PARP-1-/-) mice. Next, I will analyze PARP-1 inhibition as a potential mechanism of PZA by correlating PARP-1 activity with the effects of PZA in macrophage and mouse models of TB infection. Lastly, I will evaluate the efficacy of talazoparib, a potent PARP-1/2 inhibitor already in Phase 3 clinical development, as a novel host-directed adjunct therapy to standard TB therapy. Results from the proposed study will validate PARP-1 as a key host target of the TB drug PZA and determine if PARP-1 inhibition presents a viable but unexplored strategy to improving the treatment of TB. A better understanding of PARP-1 and PZA in Mtb infection promises new insight into the mechanisms involved in pathogenesis and disease control and could lead to new therapies for the treatment of drug-susceptible as well as drug-resistant strains of Mtb.

Public Health Relevance

Tuberculosis (TB) kills nearly 2 million people every year and is becoming increasingly resistant to the available drugs. Since Mycobacterium tuberculosis (Mtb), the bacterium that causes TB, manipulates host immune responses to ensure its survival within the host, interventions that modulate host immune responses may enhance an individual?s ability to control Mtb infection or make Mtb more sensitive to killing by TB drugs. I recently demonstrated that the TB drug pyrazinamide inhibits a key host immune regulator called PARP-1 and will evaluate PARP-1 inhibition as novel host-directed therapy that may improve the treatment of TB.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31HL140812-02
Application #
9658367
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Caler, Elisabet V
Project Start
2018-01-03
Project End
2020-01-02
Budget Start
2019-01-03
Budget End
2020-01-02
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205