Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin.

ABSTRACT: Inducible nitric oxide synthase (iNOS) plays a crucial role in controlling growth of Mycobacterium tuberculosis (M.tb), presumably via nitric oxide (NO) mediated killing. Here we show that leukocyte-specific deficiency of NO production, through targeted loss of the iNOS cofactor tetrahydrobiopterin (BH4), results in enhanced control of M.tb infection; by contrast, loss of iNOS renders mice susceptible to M.tb. By comparing two complementary NO-deficient models, Nos2^-/- mice and BH4 deficient Gch1^fl/flTie2cre mice, we uncover NO-independent mechanisms of anti-mycobacterial immunity. In both murine and human leukocytes, decreased Gch1 expression correlates with enhanced cell-intrinsic control of mycobacterial infection in vitro. Gene expression analysis reveals that Gch

SUBMITTER: McNeill E 

PROVIDER: S-EPMC6302098 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature