Reduced susceptibility of clinical strains of Mycobacterium tuberculosis to reactive nitrogen species promotes survival in activated macrophages

Idh, Jonna; Andersson, Blanka; Lerm, Maria; Raffetseder, Johanna; Eklund, Daniel; Woksepp, Hanna; Werngren, Jim; Mansjö, Mikael; Sundqvist, Tommy; Stendahl, Olle; Schӧn, Thomas

doi:10.1371/journal.pone.0181221

Cited by 14 publications

(6 citation statements)

References 38 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is a precedence that mycobacteria primed by exposure to oxidative stress have enhanced survival in the host [ 65 , 66 ]. This is, in part, due to two well described virulence factors, catalase (KatG) and alkylhydroperoxide reductase (AhpC), critical elements of the antioxidant defense system, whose expression is induced by oxidative stress and correlates with enhanced survival and hypervirulence in animal models [ 34 , 44 , 45 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

Zinc limitation triggers anticipatory adaptations in Mycobacterium tuberculosis

et al. 2021

View full text Add to dashboard Cite

Mycobacterium tuberculosis (Mtb) has complex and dynamic interactions with the human host, and subpopulations of Mtb that emerge during infection can influence disease outcomes. This study implicates zinc ion (Zn2+) availability as a likely driver of bacterial phenotypic heterogeneity in vivo. Zn2+ sequestration is part of “nutritional immunity”, where the immune system limits micronutrients to control pathogen growth, but this defense mechanism seems to be ineffective in controlling Mtb infection. Nonetheless, Zn2+-limitation is an environmental cue sensed by Mtb, as calprotectin triggers the zinc uptake regulator (Zur) regulon response in vitro and co-localizes with Zn2+-limited Mtb in vivo. Prolonged Zn2+ limitation leads to numerous physiological changes in vitro, including differential expression of certain antigens, alterations in lipid metabolism and distinct cell surface morphology. Furthermore, Mtb enduring limited Zn2+ employ defensive measures to fight oxidative stress, by increasing expression of proteins involved in DNA repair and antioxidant activity, including well described virulence factors KatG and AhpC, along with altered utilization of redox cofactors. Here, we propose a model in which prolonged Zn2+ limitation defines a population of Mtb with anticipatory adaptations against impending immune attack, based on the evidence that Zn2+-limited Mtb are more resistant to oxidative stress and exhibit increased survival and induce more severe pulmonary granulomas in mice. Considering that extracellular Mtb may transit through the Zn2+-limited caseum before infecting naïve immune cells or upon host-to-host transmission, the resulting phenotypic heterogeneity driven by varied Zn2+ availability likely plays a key role during early interactions with host cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Zinc limitation triggers anticipatory adaptations in Mycobacterium tuberculosis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Increased mycobacterial NADH/NAD + ratio, through mutation of ndh, which encodes a type II NADH dehydrogenase, exhibits co-resistance to isoniazid and ethionamide [95]. Mtb strains that show resistance to isoniazid also exhibit more resistance to ROS compared to the wild-type Mtb (CDC1551 and CB3.3) strains [96,97]. It has also been observed that these strains have increased resistance to peroxide and acidified nitrite molecules [96,98].…”

Section: Oxidative Stress and Tbmentioning

confidence: 99%

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation

et al. 2020

View full text Add to dashboard Cite

Tuberculosis (TB) is one of the leading causes of mortality and morbidity, particularly in developing countries, presenting a major threat to the public health. The currently recommended long term treatment regimen with multiple antibiotics is associated with poor patient compliance, which in turn, may contribute to the emergence of multi-drug resistant TB (MDR-TB). The low global treatment efficacy of MDR-TB has highlighted the necessity to develop novel treatment options. Host-directed therapy (HDT) together with current standard anti-TB treatments, has gained considerable interest, as HDT targets novel host immune mechanisms. These immune mechanisms would otherwise bypass the antibiotic bactericidal targets to kill Mycobacterium tuberculosis (Mtb), which may be mutated to cause antibiotic resistance. Additionally, host-directed therapies against TB have been shown to be associated with reduced lung pathology and improved disease outcome, most likely via the modulation of host immune responses. This review will provide an update of host-directed therapies and their mechanism(s) of action against Mycobacterium tuberculosis.

show abstract

“…Mechanistically, among all the ROS, nitric oxide (NO) is known to be one of the major contributors as an anti-TB agent. NO is synthesized by NO synthase in macrophages, and NO synthase-deficient mice have been shown to exhibit increased susceptibility to M. tuberculosis [ 36 ]. Patients with active pulmonary TB have higher levels of NO in their lungs [ 36 ].…”

Section: Oxidative Stress Response Against Mycobacteriummentioning

confidence: 99%

“…NO is synthesized by NO synthase in macrophages, and NO synthase-deficient mice have been shown to exhibit increased susceptibility to M. tuberculosis [ 36 ]. Patients with active pulmonary TB have higher levels of NO in their lungs [ 36 ]. The accumulation of ROS during OS can further produce superoxide, hydrogen peroxide, and hydroxyl radicals via single-electron reduction chain reactions [ 32 ].…”

Section: Oxidative Stress Response Against Mycobacteriummentioning

confidence: 99%

“…For instance, an increase in the mycobacterial NADH/NAD + ratio, through mutation of ndh which encodes a type II NADH dehydrogenase, confers coresistance to isoniazid and ethionamide [ 57 ]. M. tuberculosis strains that exhibit resistance to isoniazid and pretomanid also demonstrate higher resistance to ROS compared to wild-type M. tuberculosis (CDC1551 and CB3.3) [ 34 , 36 , 58 ]. These strains were also found to have increased resistance towards peroxide and acidified nitrite [ 35 , 58 ].…”

Section: Mechanisms Of Oxidative Stress Tolerance and Drug Resistamentioning

confidence: 99%

See 1 more Smart Citation

Role of Oxidative Stress in the Pathology and Management of Human Tuberculosis

Shastri

Shukla

Chong

et al. 2018

Oxidative Medicine and Cellular Longevity

117

View full text Add to dashboard Cite

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, is the leading cause of mortality worldwide due to a single infectious agent. The pathogen spreads primarily via aerosols and especially infects the alveolar macrophages in the lungs. The lung has evolved various biological mechanisms, including oxidative stress (OS) responses, to counteract TB infection. M. tuberculosis infection triggers the generation of reactive oxygen species by host phagocytic cells (primarily macrophages). The development of resistance to commonly prescribed antibiotics poses a challenge to treat TB; this commonly manifests as multidrug resistant tuberculosis (MDR-TB). OS and antioxidant defense mechanisms play key roles during TB infection and treatment. For instance, several established first-/second-line antitubercle antibiotics are administered in an inactive form and subsequently transformed into their active form by components of the OS responses of both host (nitric oxide, S-oxidation) and pathogen (catalase/peroxidase enzyme, EthA). Additionally, M. tuberculosis has developed mechanisms to survive high OS burden in the host, including the increased bacterial NADH/NAD+ ratio and enhanced intracellular survival (Eis) protein, peroxiredoxin, superoxide dismutases, and catalases. Here, we review the interplay between lung OS and its effects on both activation of antitubercle antibiotics and the strategies employed by M. tuberculosis that are essential for survival of both drug-susceptible and drug-resistant bacterial subtypes. We then outline potential new therapies that are based on combining standard antitubercular antibiotics with adjuvant agents that could limit the ability of M. tuberculosis to counter the host's OS response.

show abstract

Reduced susceptibility of clinical strains of Mycobacterium tuberculosis to reactive nitrogen species promotes survival in activated macrophages

Cited by 14 publications

References 38 publications

Zinc limitation triggers anticipatory adaptations in Mycobacterium tuberculosis

Zinc limitation triggers anticipatory adaptations in Mycobacterium tuberculosis

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation

Role of Oxidative Stress in the Pathology and Management of Human Tuberculosis

Contact Info

Product

Resources

About