Effects of Glutathione Diminishment on the Immune Responses against Mycobacterium tuberculosis Infection

Abstract

Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), continues to be a global health burden. We have reported that patients with marked deficiency in the production of glutathione (GSH) had impaired granulomatous effector responses against M. tb infection, which were restored when supplementing patients with liposomal GSH (lGSH). However, the effects of GSH deficiency in the lung parenchyma in altering granuloma formation and effector responses against M. tb infection remain unexplored. We aim to elucidate the effects of diethyl maleate (DEM)-induced GSH deficiency during an active M. tb infection in an in vivo mouse model. We assessed for total and reduced GSH levels, malondialdehyde (MDA) levels, cytokine profiles, granuloma formation and M. tb burden. DEM administration significantly diminished total and reduced GSH levels in the lungs and plasma and increased MDA levels in infected mice compared to sham-treated controls. DEM treatment was also associated with an increase in IL-6, TNF-α and ill-formed granulomas in infected mice. Furthermore, M. tb survival was significantly increased along with a higher pulmonary and extrapulmonary bacterial load following DEM treatment. Overall, GSH deficiency led to increased oxidative stress, impaired granuloma response, and increased M. tb survival in infected mice. These findings can provide insight into how GSH deficiency can interfere with the control of M. tb infection and avenues for novel therapeutic approaches.

GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection

“…Nonetheless, the pronounced phenotype of these mice revealed a major role for Gpx4 in regulating host resistance to Mtb infection. This conclusion is consistent with previous data demonstrating increased susceptibility of mice to Mtb infection upon drug-induced GSH deficiency ( Cao et al, 2021 ) and with a number of other studies demonstrating decreased resistance to other infectious agents in mice with genetic or drug-induced defects in glutathione metabolism ( Kang et al, 2018 ; Matsushita et al, 2015 ; Smulan et al, 2021 ; Villa et al, 2002 ). The findings presented here with Mtb infection provide a striking genetic demonstration of the powerful role this pathway can play in protecting the host from the lethal effects of excessive cellular stress.…”

“…The results presented here support an important role for the Gpx4-dependent glutathione metabolic pathway in the regulation of Mtb-induced necrosis and implicate this process as a potential target for host-directed therapy of tuberculosis. In this regard, glutathione itself has been shown to regulate Mtb infection outcomes in several murine experimental and clinical TB studies ( Cao et al, 2021 ; Guerra et al, 2011 ; Morris et al, 2013 ; Safe et al, 2020a ; Safe et al, 2020b ; To et al, 2021 ; Venketaraman et al, 2008 ; Venketaraman et al, 2006 ), but to the best of our knowledge glutathione administration, in its reduced form, has never been tested in a formal clinical trial in TB patients. In terms of Gpx4 itself, any HDT specifically targeting this enzyme would have to increase rather than inhibit its activity to be an effective therapy.…”

BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility

“…We have previously shown that Gpx4 expression is fundamental for host resistance to Mtb infection in vivo and in vitro by preventing the exacerbation of oxidative stress 13 . The findings presented here are consistent with these observations as well as previous reports demonstrating an important role for GSH metabolism in regulating host resistance to Mtb infection 12,47 . While our previous and current work have demonstrated major functions for Gpx4 in host resistance to TB, the enzyme itself is probably a poor target for host-directed therapy of TB, since its depletion or inhibition results in worsened disease outcomes.…”

Erythrocytes as Messengers for Information and Energy Exchange between Cells

“…Erythrocyte export of glutathione takes place by multi-drug resistance proteins [24]. Extracellular glutathione is of relevance in inflammation and disease [25][26][27] and can directly regulate immune components in plasma [28]. Intracellular glutathione concentration is usually three orders of magnitude higher than the extracellular glutathione concentration, and an energy-consuming active glutathione uptake mechanism seems not to be known [29].…”