Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin

Eileen McNeill*, Elena Stylianou, Mark J. Crabtree, Rachel Harrington-Kandt, Anna Lena Kolb, Marina Diotallevi, Ashley B. Hale, Paulo Bettencourt, Rachel Tanner, Matthew K. O’Shea, Magali Matsumiya, Helen Lockstone, Julius Müller, Helen A. Fletcher, David R. Greaves, Helen McShane, Keith M. Channon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

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 Gch1fl/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 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.
Original languageEnglish
Article number5409
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018
Externally publishedYes

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