Host regulator PARP1 contributes to sex differences and immune responses in a mouse model of tuberculosis

Abstract

Tuberculosis (TB) is a devastating infectious disease responsible for nearly 2 million deaths annually that has a poorly understood male bias. Elucidating the basis of this male bias may enable precision medicine interventions for TB treatment and prevention. Here, we identify the master regulator Poly(ADP-ribose) Polymerase 1 (PARP1) as a driver of TB sex differences. We found that infection with M. tuberculosis (M. tb) triggers robust PARP activation in mouse lungs, suggesting that PARP1 activation is a fundamental host response to TB. Remarkably, PARP1 deletion abolished known sex differences in TB cytokine responses and blunted the early induction of TNFα, IL-1ß, IFNγ, MCP-1, and IL-6, particularly in male mice. In contrast, PARP1 was required for IL-10 induction in male or female mice. PARP1 deletion was protective against TB in female mice, resulting in significantly prolonged survival and reduced bacterial burden, but impaired TB containment in male mice. Our findings indicate that PARP1 contributes to TB sex differences via sexually divergent immune regulation and uniquely enhances early proinflammatory responses in males that prove beneficial for TB containment.

Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages

“…PARPs are host proteins involved in cellular processes acting via PARylation of their targets. It has recently been shown that PARP1 activation is triggered in mouse lungs upon Mtb infection (27). Importantly, genetic PARP1 depletion resulted in decreased lung bacterial burden in female mice.…”

“…after overnight infection), which is an experimental setup that we generally use for the identification of novel HDT compounds (18,20,60). Although applying other compound concentrations, repeated doses or a longer treatment exposure could have resulted in a bigger effect size, the host targets (PARP and LDH) that we identified in our in vitro human macrophage model were recently published as host targets using in vivo mouse models as discussed above (27,58). This agreeing set of independent findings underscores the power and validity of our approach, which aims to decipher novel pathways involved in host defense against intracellular bacterial infections in humans, and develop corresponding novel HDT.…”

PAR level mediates the link between ROS and inflammatory response in patients with type 2 diabetes mellitus

“…In effect, PARP-1 enzyme is reported to act as a coactivator of transcription factors, such as NF-κB, AP1, and AP2, promoting the development of inflammatory processes through the upregulation of various inflammatory mediators, including TNF-α , MCP1 , and several interleukins like IL6 [ [59] , [60] , [61] , [62] , [63] , [64] ]. Accordingly, we observed that higher PAR levels are associated with increased expression of IL6 , TNF-α and MCP1 in PBMC from T2DM patients.…”

Gene Expression in Cord Blood and Tuberculosis in Early Childhood: A Nested Case-Control Study in a South African Birth Cohort

“…Among early TST converters, the top DEGs between those who did and did not progress to TB include PARP1 and KLRD1 . PARP1 has been implicated in mouse experiments, plays a fundamental role in the host response to TB, and is hypothesized to contribute to the sex differences in response to TB [ 38 ]. KLRD1 has been demonstrated to be a potential T-cell–linked biomarker in the progression to TB in mice and macaques [ 39 , 40 ].…”