TY - JOUR
T1 - Heme oxygenase-1 regulates inflammation and mycobacterial survival in human macrophages during mycobacterium tuberculosis infection
AU - Scharn, Caitlyn R.
AU - Collins, Angela C.
AU - Nair, Vidhya R.
AU - Stamm, Chelsea E.
AU - Marciano, Denise K.
AU - Graviss, Edward A.
AU - Shiloh, Michael U.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants RO1 AI099439, R21 AI111023, and U19 AI109725 (to M.U.S.), T32 AI5284 (to C.R.S.), T32 AI7520 (to C.E.S.), R01 DK099478 (to D.K.M.), and R01 DA09238 (to E.A.G.). Clinical specimens used for this project were partially supported by the National Institutes of Health (National Institute of Allergy and Infectious Diseases) under Contract N01-AO02738. M.U.S. acknowledges support from the Disease Oriented Clinical Scholars Program at University of Texas Southwestern.
Publisher Copyright:
Copyright © 2016 by The American Association of Immunologists, Inc.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1500434
DO - 10.4049/jimmunol.1500434
M3 - Article
C2 - 27183573
AN - SCOPUS:84975125166
VL - 196
SP - 4641
EP - 4649
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 11
ER -