Leishmania major: Reactive oxygen species and interferon gamma induction by soluble lipophosphoglycan of stationary phase promastigotes

2006 ◽  
Vol 114 (4) ◽  
pp. 323-328 ◽  
Author(s):  
Gholamreza Kavoosi ◽  
Sussan K. Ardestani ◽  
Amina Kariminia ◽  
Mohssen Abolhassani ◽  
Salvatore J. Turco
Keyword(s):  
Reactive Oxygen Species ◽  
Stationary Phase ◽  
Interferon Gamma ◽  
Leishmania Major ◽  
Reactive Oxygen ◽  
Oxygen Species

scholarly journals Interaction of Interferon Gamma-Induced Reactive Oxygen Species with Ceftazidime Leads to Synergistic Killing of Intracellular Burkholderia pseudomallei

2014 ◽  
Vol 58 (10) ◽  
pp. 5954-5963 ◽  
Author(s):  
Kara Mosovsky ◽  
Ediane Silva ◽  
Ryan Troyer ◽  
Katie Propst-Graham ◽  
Steven Dow
Keyword(s):  
Reactive Oxygen Species ◽  
Interferon Gamma ◽  
Burkholderia Pseudomallei ◽  
Actin Polymerization ◽  
Reactive Oxygen ◽  
Buthionine Sulfoximine ◽  
Oxygen Species ◽  
Intracellular Killing ◽  
Content Type ◽  
Ifn Γ

ABSTRACTBurkholderia pseudomallei, a facultative intracellular pathogen, causes severe infections and is inherently refractory to many antibiotics. Previous studies from our group have shown that interferon gamma (IFN-γ) interacts synergistically with the antibiotic ceftazidime to kill bacteria in infected macrophages. The present study aimed to identify the underlying mechanism of that interaction. We first showed that blocking reactive oxygen species (ROS) pathways reversed IFN-γ- and ceftazidime-mediated killing, which led to our hypothesis that IFN-γ-induced ROS interacted with ceftazidime to synergistically killBurkholderiabacteria. Consistent with this hypothesis, we also observed that buthionine sulfoximine (BSO), another inducer of ROS, could substitute for IFN-γ to similarly potentiate the effect of ceftazidime on intracellular killing. Next, we observed that IFN-γ induced ROS-mediated killing of intracellular but not extracellular bacteria. On the other hand, ceftazidime effectively reduced extracellular bacteria but was not capable of intracellular killing when applied at 10 μg/ml. We investigated the exact role of IFN-γ-induced ROS responses on intracellular bacteria and notably observed a lack of actin polymerization associated withBurkholderiabacteria in IFN-γ-treated macrophages, which led to our finding that IFN-γ-induced ROS blocks vacuolar escape. Based on these results, we propose a model in which synergistically reduced bacterial burden is achieved primarily through separate and compartmentalized killing: intracellular killing by IFN-γ-induced ROS responses and extracellular killing by ceftazidime. Our findings suggest a means of enhancing antibiotic activity againstBurkholderiabacteria through combination with drugs that induce ROS pathways or otherwise target intracellular spread and/or replication of bacteria.

Leishmania major: Effects of proteophosphoglycan on reactive oxygen species, IL-12, IFN-γ and IL-10 production in healthy individuals

2008 ◽  
Vol 120 (1) ◽  
pp. 62-66 ◽  
Author(s):  
Gholamreza Kavoosi ◽  
Sussan K. Ardestani ◽  
Amina Kariminia ◽  
Majid Zeinali ◽  
Mohammad Hossein Alimohammadian
Keyword(s):  
Reactive Oxygen Species ◽  
Leishmania Major ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Healthy Individuals ◽  
Ifn Γ

scholarly journals Interferon-gamma induced cell death: Regulation and contributions of nitric oxide, cJun N-terminal kinase, reactive oxygen species and peroxynitrite

2014 ◽  
Vol 1843 (11) ◽  
pp. 2645-2661 ◽  
Author(s):  
Srabanti Rakshit ◽  
Bhagawat S. Chandrasekar ◽  
Banishree Saha ◽  
Emmanuel S. Victor ◽  
Shamik Majumdar ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Interferon Gamma ◽  
Reactive Oxygen ◽  
Oxygen Species

scholarly journals Role of Bacillus subtilis DNA Glycosylase MutM in Counteracting Oxidatively Induced DNA Damage and in Stationary-Phase-Associated Mutagenesis

2015 ◽  
Vol 197 (11) ◽  
pp. 1963-1971 ◽  
Author(s):  
Martha Gómez-Marroquín ◽  
Luz E. Vidales ◽  
Bernardo N. Debora ◽  
Fernando Santos-Escobar ◽  
Armando Obregón-Herrera ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Bacillus Subtilis ◽  
Stationary Phase ◽  
Reactive Oxygen ◽  
Dna Glycosylase ◽  
Oxygen Species ◽  
Content Type

ABSTRACTReactive oxygen species (ROS) promote the synthesis of the DNA lesion 8-oxo-G, whose mutagenic effects are counteracted in distinct organisms by the DNA glycosylase MutM. We report here that inBacillus subtilis,mutMis expressed during the exponential and stationary phases of growth. In agreement with this expression pattern, results of a Western blot analysis confirmed the presence of MutM in both stages of growth. In comparison with cells of a wild-type strain, cells ofB. subtilislacking MutM increased their spontaneous mutation frequency to Rifrand were more sensitive to the ROS promoter agents hydrogen peroxide and 1,1′-dimethyl-4,4′-bipyridinium dichloride (Paraquat). However, despite MutM's proven participation in preventing ROS-induced-DNA damage, the expression ofmutMwas not induced by hydrogen peroxide, mitomycin C, or NaCl, suggesting that transcription of this gene is not under the control of the RecA, PerR, or σBregulons. Finally, the role of MutM in stationary-phase-associated mutagenesis (SPM) was investigated in the strainB. subtilisYB955 (hisC952 metB5 leuC427). Results revealed that under limiting growth conditions, amutMknockout strain significantly increased the amount of stationary-phase-associatedhis,met, andleurevertants produced. In summary, our results support the notion that the absence of MutM promotes mutagenesis that allows nutritionally stressedB. subtiliscells to escape from growth-limiting conditions.IMPORTANCEThe present study describes the role played by a DNA repair protein (MutM) in protecting the soil bacteriumBacillus subtilisfrom the genotoxic effects induced by reactive oxygen species (ROS) promoter agents. Moreover, it reveals that the genetic inactivation ofmutMallows nutritionally stressed bacteria to escape from growth-limiting conditions, putatively by a mechanism that involves the accumulation and error-prone processing of oxidized DNA bases.

scholarly journals Sterol 14-α-demethylase is vital for mitochondrial functions and stress tolerance in Leishmania major

2020 ◽  
Author(s):  
Sumit Mukherjee ◽  
Samrat Moitra ◽  
Wei Xu ◽  
Veronica Hernandez ◽  
Kai Zhang
Keyword(s):  
Reactive Oxygen Species ◽  
Plasma Membrane ◽  
Leishmania Major ◽  
Reactive Oxygen ◽  
Sterol Synthesis ◽  
Heat Sensitivity ◽  
Oxygen Species ◽  
Chemical Inactivation ◽  
Cellular Processes ◽  
Intracellular Organelles

ABSTRACTSterol 14-α-demethylase (C14DM) is a key enzyme in the biosynthesis of sterols and the primary target of azoles. In Leishmania major, genetic or chemical inactivation of C14DM leads to accumulation of 14-methylated sterol intermediates and profound plasma membrane abnormalities including increased fluidity and failure to maintain ordered membrane microdomains. These defects likely contribute to the hypersensitivity to heat and severely reduced virulence displayed by the C14DM-null mutants (c14dm-). In addition to plasma membrane, sterols are present in intracellular organelles. In this study, we investigated the impact of C14DM ablation on mitochondria. Our results demonstrate that c14dm- mutants have significantly higher mitochondrial membrane potential than wild type parasites. Such high potential leads to the buildup of reactive oxygen species in the mitochondria, especially under nutrient-limiting conditions. Consistent with these mitochondrial alterations, c14dm- mutants show impairment in respiration and are heavily dependent on glucose uptake and glycolysis to generate energy. Consequently, these mutants are extremely sensitive to glucose deprivation and such vulnerability can be rescued through the supplementation of glucose or glycerol. In addition, the accumulation of oxidants may also contribute to the heat sensitivity exhibited by c14dm-. Finally, genetic or chemical ablation of C14DM causes increased susceptibility to pentamidine, an antimicrobial agent with activity against trypanosomatids. In summary, our investigation reveals that alteration of sterol synthesis can negatively affect multiple cellular processes in Leishmania parasites and make them vulnerable to clinically relevant stress conditions.AUTHOR SUMMARYSterols are well recognized for their stabilizing effects on the plasma membrane, but their functions in intracellular organelles are under explored, which hampers the development of sterol synthesis inhibitors as drugs. Our previous studies have demonstrated significant plasma membrane instability in the sterol biosynthetic mutant c14dm- in Leishmania major, a pathogenic protozoan responsible for cutaneous leishmaniasis causing 1-1.5 million infections a year. While the plasma membrane defects have undoubtedly contributed to the reduced virulence exhibited by c14dm- mutants, it was not clear whether other cellular processes were also affected. In this study, we revealed profound mitochondrial dysfunctions and elevated level of reactive oxygen species in c14dm- mutants. These sterol mutants rely heavily on glycolysis to generate energy and are extremely sensitive to glucose restriction. In addition, the accumulation of oxidants appears to be responsible (at least in part) for the previously observed heat sensitivity in c14dm- mutants. Thus, genetic or chemical inactivation of C14DM can influence the functions of cellular organelles beyond the plasma membrane. These findings shed light on the mechanism of action for azole compounds and provide new insight into the roles of sterol biosynthesis in Leishmania parasites.

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