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L-Citrulline Metabolism Orchestrates Anti-mycobacterial Immunity

Lange, Shannon Marie
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511882575584058

Abstract Details

2017, PhD, University of Cincinnati, Medicine: Immunology.
Mycobacterial disease plagues over one-third of the global population. The most devastating of which – Mycobacterium tuberculosis – kills more than 1.5 million annually and multi-drug resistance increases its catastrophic reach. Host-directed therapy is a promising counter-balance against drug resistant mycobacteria, warranting further investigation into anti-mycobacterial host defense. Key immune populations –macrophages and T cells – are regulated by the availability of the amino acid L-arginine. Nitric oxide (NO), a potent anti-mycobacterial agent deployed by macrophages, and appropriate Th1 functions – e.g. proliferation, IFN-γ production – demand L-arginine. However, mycobacterial infection restricts L-arginine by inducing myeloid arginase, resulting in diminished NO production by macrophages and hyporesponsive T cells. Previously, our group found that synthesis of L-arginine from the endogenous precursor, L-citrulline, is a necessary metabolic pathway for anti-mycobacterial immunity, but the mechanism of action within the immune population was unknown. Herein, we define the immunological consequences of L-citrulline metabolism during mycobacterial infection. We found that L-citrulline metabolism endows macrophages and T cells with a mechanism to circumvent arginase-mediated inhibition of anti-mycobacterial function in vitro. Utilizing novel mouse models of L-citrulline metabolism deficiency, we uncovered an unappreciated necessity of L-citrulline metabolism for macrophage and T cell immunity to mycobacterial infection in vivo. Additionally, our data show that mice supplemented with L-citrulline exhibit enhanced control of pulmonary M. bovis BCG infection compared to vehicle-treated controls, revealing the potential of this metabolic pathway as a novel therapeutic to combat mycobacterial disease.
Joseph Qualls, Ph.D. (Committee Chair)
Claire Chougnet, Ph.D. (Committee Member)
George Deepe, M.D. (Committee Member)
David Haslam, M.D. (Committee Member)
Edith Janssen, Ph.D. (Committee Member)
218 p.
Immunology
L-citrulline; L-arginine; immunometabolism; mycobacterium; ass1; asl

Recommended Citations

Citations

  • Lange, S. M. (2017). L-Citrulline Metabolism Orchestrates Anti-mycobacterial Immunity [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511882575584058

    APA Style (7th edition)

  • Lange, Shannon. L-Citrulline Metabolism Orchestrates Anti-mycobacterial Immunity. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511882575584058.

    MLA Style (8th edition)

  • Lange, Shannon. "L-Citrulline Metabolism Orchestrates Anti-mycobacterial Immunity." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511882575584058

    Chicago Manual of Style (17th edition)

ucin1511882575584058
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© 2017, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.