McNeill, E, Stylianou, E, Crabtree, MJ, Harrington-Kandt, R, Kolb, A, Diotallevi, M, Hale, AB, Bettencourt, P, Tanner, R, O’Shea, MK, Matsumiya, M, Lockstone, H, Müller, J, Fletcher, HA, Greaves, DR, McShane, H and Channon, KM. 2018. Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin. [Online]. Nature Communications. Available from: https://doi.org/10.1038/s41467-018-07714-9
McNeill, E, Stylianou, E, Crabtree, MJ, Harrington-Kandt, R, Kolb, A, Diotallevi, M, Hale, AB, Bettencourt, P, Tanner, R, O’Shea, MK, Matsumiya, M, Lockstone, H, Müller, J, Fletcher, HA, Greaves, DR, McShane, H and Channon, KM. Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin [Internet]. Nature Communications; 2018. Available from: https://doi.org/10.1038/s41467-018-07714-9
McNeill, E, Stylianou, E, Crabtree, MJ, Harrington-Kandt, R, Kolb, A, Diotallevi, M, Hale, AB, Bettencourt, P, Tanner, R, O’Shea, MK, Matsumiya, M, Lockstone, H, Müller, J, Fletcher, HA, Greaves, DR, McShane, H and Channon, KM (2018). Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin. [Data Collection]. Nature Communications. https://doi.org/10.1038/s41467-018-07714-9
Description
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.
| Data capture method | Experiment |
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| Date (Date published in a 3rd party system) | 20 December 2018 |
| Language(s) of written materials | English |
| Data Creators | McNeill, E, Stylianou, E, Crabtree, MJ, Harrington-Kandt, R, Kolb, A, Diotallevi, M, Hale, AB, Bettencourt, P, Tanner, R, O’Shea, MK, Matsumiya, M, Lockstone, H, Müller, J, Fletcher, HA, Greaves, DR, McShane, H and Channon, KM |
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| LSHTM Faculty/Department | Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection |
| Participating Institutions | London School of Hygiene & Tropical Medicine |
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| Date Deposited | 24 Jul 2019 09:49 |
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| Last Modified | 08 Jul 2021 12:49 |
| Publisher | Nature Communications |
