TY - JOUR
T1 - Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin
AU - McNeill, Eileen
AU - Stylianou, Elena
AU - Crabtree, Mark J.
AU - Harrington-Kandt, Rachel
AU - Kolb, Anna Lena
AU - Diotallevi, Marina
AU - Hale, Ashley B.
AU - Bettencourt, Paulo
AU - Tanner, Rachel
AU - O’Shea, Matthew K.
AU - Matsumiya, Magali
AU - Lockstone, Helen
AU - Müller, Julius
AU - Fletcher, Helen A.
AU - Greaves, David R.
AU - McShane, Helen
AU - Channon, Keith M.
N1 - Funding Information:
This work was supported by the British Heart Foundation [RG/15/10/31485], [RG/17/10/32859] and [CH/16/1/32013], Wellcome Trust [095780/Z/11/Z] and [203141/Z/16/Z], The John Fell Fund, The Oxford University Medical Research Fund, and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. BCG-GFP was a gift from Rajko Reljic from St. George’s University of London (SGUL).
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85058874998&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-07714-9
DO - 10.1038/s41467-018-07714-9
M3 - Article
C2 - 30573728
AN - SCOPUS:85058874998
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5409
ER -