title: Heme Oxygenase-1 Regulates Inflammation and Mycobacterial Survival in Human Macrophages during Mycobacterium tuberculosis Infection.
abstract: Mycobacterium tuberculosis, the causative agent of tuberculosis, is responsible for 1.5 million deaths annually. We previously showed that M. tuberculosis infection in mice induces expression of the CO-producing enzyme heme oxygenase (HO1) and that CO is sensed by M. tuberculosis to initiate a dormancy program. Further, mice deficient in HO1 succumb to M. tuberculosis infection more readily than do wild-type mice. Although mouse macrophages control intracellular M. tuberculosis infection through several mechanisms, such as NO synthase, the respiratory burst, acidification, and autophagy, how human macrophages control M. tuberculosis infection remains less well understood. In this article, we show that M. tuberculosis induces and colocalizes with HO1 in both mouse and human tuberculosis lesions in vivo, and that M. tuberculosis induces and colocalizes with HO1 during primary human macrophage infection in vitro. Surprisingly, we find that chemical inhibition of HO1 both reduces inflammatory cytokine production by human macrophages and restricts intracellular growth of mycobacteria. Thus, induction of HO1 by M. tuberculosis infection may be a mycobacterial virulence mechanism to enhance inflammation and bacterial growth.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Caitlyn R
authors.initials: CR
authors.lastname: Scharn
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Angela C
authors.identifier: 0000-0001-6392-7151
authors.initials: AC
authors.lastname: Collins
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Vidhya R
authors.initials: VR
authors.lastname: Nair
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Chelsea E
authors.initials: CE
authors.lastname: Stamm
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Denise K
authors.identifier: 0000-0003-0612-4664
authors.initials: DK
authors.lastname: Marciano
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX 77030; and.
authors.forename: Edward A
authors.identifier: 0000-0003-1024-5813
authors.initials: EA
authors.lastname: Graviss
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390 Michael.Shiloh@UTSouthwestern.edu.
authors.forename: Michael U
authors.identifier: 0000-0003-4329-2253
authors.initials: MU
authors.lastname: Shiloh
mesh_terms: D000818:Animals; D002460:Cell Line; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D014376:Tuberculosis / Q000378:metabolism* / Q000382:microbiology*; D020298:U937 Cells
chemical_list: D051547:Heme Oxygenase-1