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 and Keith M. Channon ()
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Eileen McNeill: John Radcliffe Hospital, University of Oxford
Elena Stylianou: University of Oxford
Mark J. Crabtree: John Radcliffe Hospital, University of Oxford
Rachel Harrington-Kandt: University of Oxford
Anna-Lena Kolb: John Radcliffe Hospital, University of Oxford
Marina Diotallevi: John Radcliffe Hospital, University of Oxford
Ashley B. Hale: John Radcliffe Hospital, University of Oxford
Paulo Bettencourt: University of Oxford
Rachel Tanner: University of Oxford
Matthew K. O’Shea: University of Oxford
Magali Matsumiya: University of Oxford
Helen Lockstone: University of Oxford
Julius Müller: University of Oxford
Helen A. Fletcher: London School of Hygiene and Tropical Medicine
David R. Greaves: University of Oxford
Helen McShane: University of Oxford
Keith M. Channon: John Radcliffe Hospital, University of Oxford

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07714-9

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