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

Abstract

AbstractThe protective correlates ofMycobacterium tuberculosis(Mtb) infection-elicited host immune responses are incompletely understood. Here we report pro-pathogenic crosstalk between IL-17, COX2, and Neutrophils. We show that most intracellular bacilli in the wild-type (WT) mice’s lungs are neutrophil-resident. In BCG-vaccinated WT mice,Mtbcontinues to persist inside neutrophils, which is sensitive to COX2 inhibition. Using a genetically susceptibleIFNγ-/-mice model, we report that excessive neutrophil infiltration and corresponding bacteremia are dependent on neutrophil-derived IL-17. COX2 inhibition and IL-17 neutralization reverse neutrophil infiltration, associated pathology and death inIFNγ-/-mice. The IL-17-Neutrophils interplay also operates in WT mice, and RORγt inhibition enhances BCG’s protective efficacy. In a prospective clinical cohort of pulmonary TB, high neutrophil count and IL-17 precipitate adverse treatment outcomes. We propose targeting the pro-pathogenic IL-17- Neutrophils axis to enhance TB prevention and therapy in normal and vulnerable subjects.