In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of <i>Mycobacterium tuberculosis</i>

Abstract

Significance Mycobacterium tuberculosis induces the expression of the indoleamine 2,3-dioxygenase (IDO) enzyme, which catabolizes tryptophan. Tryptophan metabolites potently suppress host immunity. The present study demonstrates that blockade of IDO activity reduces both clinical manifestations of tuberculosis (TB) as well as microbial and pathological correlates of the human TB syndrome in macaques. In granulomas, T cells localize in the periphery, and are unable to access the core, where bacilli persist. Inhibiting IDO activity altered granuloma organization such that more T cells translocated to the lesion core and exhibited highly proliferative signatures. Our results identify a highly efficient immunosuppressive mechanism at play in the granuloma environment that aids in M. tuberculosis persistence. The ability to modulate this pathway with safe and approved compounds could, however, facilitate chemotherapy-adjunctive host-directed therapy approaches for the control of TB.