Heme Oxygenase-1 Regulates Inflammation and Mycobacterial Survival in Human Macrophages during Mycobacterium tuberculosis Infection

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is responsible for 1.5 million deaths annually. We previously showed that Mtb infection in mice induces expression of the carbon monoxide (CO) producing enzyme heme oxygenase (HO1) and that CO is sensed by Mtb to initiate a dormancy program. Further, mice deficient in HO1 succumb to Mtb infection more readily than wild type mice. While mouse macrophages control intracellular Mtb infection through several mechanisms such as nitric oxide synthase, the respiratory burst, acidification and autophagy, how human macrophages control Mtb infection remains less well understood. Here we show that Mtb induces and colocalizes with HO1 in both mouse and human tuberculosis lesions in vivo, and that Mtb 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 Mtb infection may be a mycobacterial virulence mechanism to enhance inflammation and bacterial growth.

Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes

“…This conclusion is supported by a recent study demonstrating that pharmacological inhibition of HO-1 in M. tuberculosis -infected human macrophages resulted in a reduction in intracellular bacterial loads as well as decreased proinflammatory cytokine production (14). Although we at present cannot rule out possible off-target effects of SnPPIX, our data indicate that direct toxicity of the compound for M. tuberculosis itself is highly unlikely.…”

“…The latter could result from either impaired recruitment of enzyme-expressing cells to the lungs or defective induction of enzyme synthesis because of the absence of a T cell response. In this regard, macrophages and monocytes rather than T cells have been shown to be the major source of HO-1 in infected lungs of WT mice as well as human lungs (14). While purified bone marrow-derived macrophage cultures can produce HO-1 in response to M. tuberculosis infection in the absence of T cells (7), it is possible that the infected tissue macrophage subpopulations in the lungs of M. tuberculosis -exposed mice require additional T cell activation signals to achieve optimal enzyme expression in vivo .…”

Rv2074 is a novel F420H2‐dependent biliverdin reductase in Mycobacterium tuberculosis

“…Therefore, it is likely that Rv2074 reduces the excess biliverdin produced in macrophages upon mycobacterial infection due to HO upregulation, producing bilirubin for its antioxidant activity . HO upregulation has already been shown to promote M. tuberculosis and M. abscessus proliferation inside macrophages during early infection . where bilirubin itself can also have a similar protective effect on intracellular M. abscessus .…”

“…[6][7][8][9] HO upregulation has already been shown to promote M. tuberculosis and M. abscessus proliferation inside macrophages during early infection. 27,29 where bilirubin itself can also have a similar protective effect on intracellular M. abscessus. 27 The bilirubin produced by F-BVRs could form an "anti-oxidative pocket" around the bacterial cell that can quench lethal nitrosative species like NO produced by the engulfing macrophage.…”

“…73 F 420 is also known to be exported to the outer mycobacterial membrane. 74 Therefore, it is likely that Rv2074 reduces the excess biliverdin produced in macrophages upon mycobacterial infection due to HO upregulation, [27][28][29] producing bilirubin for its antioxidant activity. [6][7][8][9] HO upregulation has already been shown to promote M. tuberculosis and M. abscessus proliferation inside macrophages during early infection.…”