An IL-17-Ly6G+Polymorphonuclear Neutrophil (PMN) axis limits protective host responses against tuberculosis.
The protective correlates of Mycobacterium tuberculosis (Mtb) infection-elicited host immune responses are incompletely understood. Here we report pro-pathogenic crosstalk between IL-17, COX2, and Ly6G+Polymorphonuclear Neutrophils (PMNs). We show that most intracellular bacilli in the wild-type (WT) mice's lungs are Ly6G+PMN-resident. In BCG-vaccinated WT mice, Mtb continues to persist inside Ly6G+PMNs, which is sensitive to COX2 inhibition. Using a genetically susceptible IFN? -/- mice model, we report that excessive neutrophil infiltration and corresponding bacteremia are dependent on Ly6G+PMN-derived IL-17. COX2 inhibition and IL-17 neutralization reverses Ly6G+PMN infiltration, associated pathology and death in IFN? -/- mice. Inhibiting ROR?T along with COX2 in Mtb-infected WT mice further demonstrates the pathological nature of the IL-17- Ly6G+PMN axis. Clinically, in a prospective cohort of pulmonary TB subjects, high neutrophil count and serum IL-17 levels precipitate adverse treatment outcomes. Therefore, targeting the pro-pathogenic IL-17- Ly6G+PMN axis could enhance TB prevention and therapy in normal and genetically vulnerable subjects. Overall design: Comparative gene expression profiling analysis of RNA-seq data from Polymorphonuclear Neutrophils of Mycobacterium tuberculosis infected mice treated with BCG and/or Celecoxib and uninfected mice