
結核感染時、好中球(Ly6G+細胞)が主要な IL-17 産生源となり、COX2 を介して結核の病態進行を促進する。IL-17 と COX2 を標的にすることで、BCG ワクチンの防御効果を高められる可能性がある。


coremsg

The protective correlates of Mycobacterium tuberculosis ( Mtb ) infection-elicited host immune responses are incompletely understood. Here, we report pro-pathogenic crosstalk involving Ly6G+granulocytes (Ly6G+Gra), IL-17 and COX2. We show that in the lungs of Mtb -infected wildtype mice, either BCG-vaccinated or not, most intracellular bacilli are Ly6G+Gra-resident four weeks post-infection onwards. In the genetically susceptible IFNγ−/− mice, excessive Ly6G+Gra infiltration correlates with severe bacteraemia. Neutralizing IL-17 (anti-IL17mAb) and COX2 inhibition by celecoxib reverse Ly6G+Gra infiltration, associated pathology and death in IFNγ−/− mice. Surprisingly, Ly6G+Gra also serves as the major source of IL-17 in the lungs of Mtb -infected WT or IFNγ−/− mice. The IL-17-COX2-Ly6G+Gra interplay also operates in WT mice. Inhibiting RORγt, the key transcription factor for IL-17 production or COX2, reduces the bacterial burden in Ly6G+Gra, leading to reduced bacterial burden and pathology in the lungs of WT mice. In the Mtb -infected WT mice, COX2 inhibition abrogates IL-17 levels in the lung homogenates and significantly enhances BCG’s protective efficacy, mainly by targeting the Ly6G+Gra-resident Mtb pool. 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-Ly6G+Gra axis for TB prevention and therapy.

### Competing Interest Statement

The authors have declared no competing interest.

Ly6G+Granulocytes-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis

結核感染時の好中球由来-il-17-は宿主防御反応を抑制し-結核の病態進行を促進する


結核感染時の好中球由来 IL-17 は宿主防御反応を抑制し、結核の病態進行を促進する
