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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/fl  Tie2cre 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  Gch1  deficient macrophages have altered inflammatory response, lysosomal function, cell survival and cellular metabolism, thereby enhancing the control of bacterial infection. Our data thus highlight the importance of the NO-independent functions of  Nos2  and  Gch1  in mycobacterial control.

Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin