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Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin

Author

Listed:
  • Eileen McNeill

    (John Radcliffe Hospital, University of Oxford
    University of Oxford)

  • Elena Stylianou

    (University of Oxford)

  • Mark J. Crabtree

    (John Radcliffe Hospital, University of Oxford
    University of Oxford)

  • Rachel Harrington-Kandt

    (University of Oxford)

  • Anna-Lena Kolb

    (John Radcliffe Hospital, University of Oxford
    University of Oxford)

  • Marina Diotallevi

    (John Radcliffe Hospital, University of Oxford
    University of Oxford)

  • Ashley B. Hale

    (John Radcliffe Hospital, University of Oxford
    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
    University of Oxford)

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.

Suggested Citation

  • 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 Mat, 2018. "Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07714-9
    DOI: 10.1038/s41467-018-07714-9
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