Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin
McNeill E., Stylianou E., Crabtree MJ., Harrington-Kandt R., Kolb A-L., Diotallevi M., Hale AB., Bettencourt P., Tanner R., O’Shea MK., Matsumiya M., Lockstone H., Müller J., Fletcher HA., Greaves DR., McShane H., Channon KM.
AbstractInducible nitric oxide synthase (iNOS) plays a crucial role in controlling growth ofMycobacterium 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 ofM.tbinfection; by contrast, loss of iNOS renders mice susceptible toM.tb. By comparing two complementary NO-deficient models,Nos2−/−mice and BH4 deficientGch1fl/flTie2cre mice, we uncover NO-independent mechanisms of anti-mycobacterial immunity. In both murine and human leukocytes, decreasedGch1expression correlates with enhanced cell-intrinsic control of mycobacterial infection in vitro. Gene expression analysis reveals thatGch1deficient 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 ofNos2andGch1in mycobacterial control.