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 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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 5409 (12 20 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30573728 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biopterins
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• GTP Cyclohydrolase
• Gch1 protein, mouse
• sapropterin

Topics

• Animals
• Biopterins (analogs & derivatives, genetics, metabolism, physiology)
• Cell Survival
• GTP Cyclohydrolase (genetics, metabolism, physiology)
• Gene Deletion
• Gene Expression Profiling
• Humans
• Macrophages (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide (biosynthesis)
• Nitric Oxide Synthase Type II (genetics, metabolism, physiology)
• Tuberculosis (immunology)