Ly6Ggranulocytes-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis.

The protective correlates of() infection-elicited host immune responses are incompletely understood. Here, we report pro-pathogenic crosstalk involving Ly6Ggranulocytes (Ly6GGra), IL-17, and COX2. We show that in the lungs of-infected wild-type mice, either BCG-vaccinated or not, most intracellular bacilli are Ly6GGra-resident 4 weeks post-infection onwards. In the genetically susceptiblemice, excessive Ly6GGra infiltration correlates with severe bacteremia. Neutralizing IL-17 (anti-IL17mAb) and COX2 inhibition by celecoxib reverse Ly6GGra infiltration, associated pathology, and death inmice. Surprisingly, Ly6GGra also serves as the major source of IL-17 in the lungs of-infected WT ormice. The IL-17-COX2-Ly6GGra interplay also operates in WT mice. Inhibiting RORγt, the key transcription factor for IL-17 production or COX2, reduces the bacterial burden in Ly6GGra, leading to reduced bacterial burden and pathology in the lungs of WT mice. In the-infected WT mice, COX2 inhibition abrogates IL-17 levels in the lung homogenates and significantly enhances BCG's protective efficacy, mainly by targeting the Ly6GGra-residentpool, a phenotype also observed when IL-17 is blocked by RORγt inhibitor. Furthermore, in pulmonary TB patients, high neutrophil count and IL-17 correlated with adverse treatment outcomes. Together, our results suggest that IL-17 and PGE2 are the negative correlates of protection, and we propose targeting the pro-pathogenic IL-17-COX2-Ly6GGra axis for TB prevention and therapy.