Host immune regulator PARP1 drives TB sex differences Stefanie Krug, Bong Gu Kang, Ted M. Dawson, Valina L. Dawson, & William R. Bishai The Johns Hopkins School of Medicine, Baltimore, MD, USA Background: TB has a male bias but the underlying biological factors are poorly understood. Men not only develop active TB more frequently but also display worse severity than women, potentially due to the male-specific exaggerated inflammatory response early in infection. Elucidating the basis of the male bias in TB may enable precision medicine interventions for TB treatment and prevention. The conserved eukaryotic enzyme, Poly(ADP-ribose) Polymerase 1 (PARP1), regulates many cellular functions, including inflammatory responses, but its role in TB is so far unknown. Since PARP1 regulates sexually divergent immune responses and drives disease severity in numerous inflammatory conditions, we hypothesized that PARP1 similarly regulates the immune responses associated with TB sex differences. Methods: We quantified PARP1 activity in uninfected and TB-infected mice by PAR Western blot and characterized the role of PARP1 in TB by comparing survival, disease progression, cytokine levels and immunopathology in PARP1-/- and WT (129S1) mice. Results: TB infection robustly activates PARP1 in mouse lungs. Surprisingly, PARP1 deletion was profoundly protective against TB in female mice, resulting in significantly prolonged survival and reduced bacterial burden. In contrast, PARP1 deletion was detrimental in male mice, as indicated by significantly higher bacterial burden and lung inflammation. Remarkably, PARP1 deletion abolished sex differences in TB cytokine responses, including in TNFα, IL-1ß and IFNγ production, suggesting that PARP1 promotes proinflammatory responses specifically in males to control TB infection. Conclusions: Here, we identify the master regulator PARP1 as a driver of sexually divergent TB immune responses and propose that PARP1 contributes TB sex differences by differentially regulating male and female immune processes. In addition, we uncovered a new role of PARP1 as a host factor that contributes to the genetic susceptibility to TB.