Heme oxygenase-1 regulates inflammation and mycobacterial survival in human macrophages during M. tuberculosis infection

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.