xCT increases tuberculosis susceptibility by regulating antimicrobial function and inflammation

Abstract

The physiological functions of macrophage, which plays a central role in the pathogenesis of tuberculosis, depend on its redox state. System xc-, a cystine-glutamate transporter, which consists of xCT and CD98, influences many ROS-dependent pathways by regulating the production of the antioxidant glutathione. xCT's ability to alter this critical host redox balance by increasing the glutathione synthesis aspect of phagocyte physiology suggested that it might influence tuberculosis pathogenesis. In this study, we found that the xCT expression was increased in peripheral blood monocyte of active tuberculosis. xCT expression in macrophage was induced by Mycobacterium tuberculosis (Mtb) through TLR2/Akt- and p38-dependent signaling pathway. Importantly, xCT deficiency conferred protection against tuberculosis, as xCT knock out mice displayed increased Mtb load and reduced pulmonary pathology in lung compared to wild type mice. xCT disruption enhanced the mycobateriacidal activity of macrophage through increasing the mycothiol oxidation. Importantly, chemical inhibition of xCT with sulfasalazine, a specific xCT inhibitor that is already approved by the FDA for treatment of inflammatory bowel disease, produces similar protective effects in vivo and in vitro, indicating xCT might be a novel and useful target for host-directed TB treatment strategy.

Risk alleles for tuberculosis infection associate with reduced immune reactivity in a wild mammalian host

“…Multiscale studies can also uncover targets for treatment or intervention, by identifying genetic and immunologic mechanisms underlying variation in disease susceptibility while allowing for natural variation in hosts, microbes and environmental context. The findings presented here mirror immunological discoveries in controlled laboratory experiments in M. tuberculosis -infected mice [76–78] and human cell lines [70,79,80], substantiating the important role of IL-12 and phagocyte activation in tuberculosis progression, even outside of the laboratory. In addition, multiscale studies that link genetic variation to disease dynamics and host fitness in wild systems provide an empirical foundation for models of host–pathogen coevolutionary dynamics, sharpening our ability to predict and understand long-term changes in host–pathogen interactions.…”

Biphasic Dynamics of Macrophage Immunometabolism duringMycobacterium tuberculosisInfection

“…Indeed, findings from a recent study indicate that increased xCT expression is associated with development of active TB in humans, and that xCT -deficient C57BL/6 mice have an enhanced ability to control M. tuberculosis growth with decreased bacillary load and reduced pathology in lungs in comparison to wild-type mice (85). Based on these observations, it appears reasonable to determine whether specific xCT inhibitors, such as sulfasalazine (SASP) (86), an anti-inflammatory drug routinely used in clinical therapy, can be used as host-directed therapy (HDT) to boost host antimicrobial response during TB treatment.…”

Ibrutinib suppresses intracellular mycobacterium tuberculosis growth by inducing macrophage autophagy

“…It has been well established that appropriate activation of macrophage function as efficient killing of Mtb , while dysfunction-macrophage provides the niche for intracellular Mtb growth. [6][7][8] Consequently, HDT drug candidates targeting the functions of macrophage, especially those involved in effective control of intracellular Mtb growth such as ROS production and autophagy, have showed promising effect against both drug-sensitive and drug-resistance Mtb infection. [9][10][11] Autophagy is critical for effective control of intracellular pathogens and mainly regulated by mTOR pathway, 12 and perturbations in the autophagy network have previously been associated with Mtb virulence 13 Accordingly, several molecules that with potential to enhance autophagy has been proposed as HDT candidate against TB.…”