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

Mosovsky, Kara; Silva, Ediane; Troyer, Ryan M.; Propst-Graham, Katie; Dow, Steven

doi:10.1128/aac.02781-14

Cited by 11 publications

(21 citation statements)

References 54 publications

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“…IL‐18 was originally discovered as an IFN-γ-inducer which induces IFN-γ production from Th1 and NK cells with or without IL-12 upon stimulation with antigens 47 , 48 . IFN-γ is an important inflammatory factor which induced inflammatory response and ROS can cause cell death through apoptosis and necroptosis 49 , 50 . We tested the expression of potential synergistic mediators of IL-18 signaling, such as IL-15 and IL-12, in irradiated BM.…”

Section: Discussionmentioning

confidence: 99%

IL-18 binding protein (IL-18BP) as a novel radiation countermeasure after radiation exposure in mice

Cui

Hull

et al. 2020

Sci Rep

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Recent studies suggested that radiation exposure causes local and systemic inflammatory responses and induces cell and tissue damage. We have reported that IL-18 plays an important role in radiation-induced injury. Here, we demonstrate that IL-18 binding protein (IL-18BP), a natural antagonist of IL-18, was significantly increased (1.7–63 fold) in mouse serum on day 1 after 0.5–10 Gy TBI. However, this high level of IL-18BP was not sufficient to neutralize the active IL-18 in irradiated mice, resulting in a radiation dose-dependent free IL-18 increase in these mice’s serum which led to pathological alterations to the irradiated cells and tissues and finally caused animal death. Administration of recombinant human (rh) IL-18BP (1.5 mg/kg) with single (24, 48 or 72 h post-TBI) or double doses (48 h and 5 days post-TBI) subcutaneous (SC) injection increased 30-day survival of CD2F1 mice after 9 Gy TBI 12.5–25% compared with the vehicle control treated group, respectively. Furthermore, the mitigative effects of rhIL-18BP included balancing the ratio of IL-18/IL-18BP and decreasing the free IL-18 levels in irradiated mouse serum and significantly increasing blood cell counts, BM hematopoietic cellularity and stem and progenitor cell clonogenicity in mouse BM. Furthermore, IL-18BP treatment inhibited the IL-18 downstream target interferon (IFN)-γ expression in mouse BM, decreased reactive oxygen species (ROS) level in the irradiated mouse heart tissues, attenuated the stress responsive factor GDF-15 (growth differentiation factor-15) and increased the intestine protector citrulline level in total body irradiated mouse serum, implicating that IL-18BP may protect multiple organs from radiation-induced inflammation and oxidative stress. Our data suggest that IL-18 plays a key role in radiation-induced cell and tissue damage and dysfunction; and for the first time demonstrated that IL-18BP counters IL-18 activation and therefore may mitigate/treat radiation-induced multiple organ injuries and increase animal survival with a wider therapeutic window from 24 h and beyond after lethal doses of radiation exposure.

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Section: Discussionmentioning

confidence: 99%

IL-18 binding protein (IL-18BP) as a novel radiation countermeasure after radiation exposure in mice

Cui

Hull

et al. 2020

Sci Rep

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“…We previously found that two cellular antioxidants and ROS pathway inhibitors, N-acetylcysteine (NAC) and glutathione (GSH), abolished the synergistic effect of IFN-γ and ceftazidime to reduce intracellular bacterial burden in B. thailandensis infected macrophages [24]. These results supported the role of IFN-γ-induced ROS in contributing to the reduction of bacteria in the combination treatment of macrophages.…”

Section: Semet Treatment Of Infected Macrophages Leads To Significantmentioning

confidence: 62%

“…We had previously seen evidence of a dynamic interplay between the extracellular and intracellular spaces of our macrophage infection model [24], whereby extracellular bacteria could gain entrance to the inside compartments of macrophages, and intracellular bacteria, upon rupture or lysis of the macrophage, could exit back into the extracellular space. Such movement of bacteria between intracellular and extracellular spaces would be predicted based on the known pathogenesis of Burkholderia [4,8].…”

Section: Plos Onementioning

confidence: 99%

“…Infection assays were performed as previously described [24,25]. Macrophages were washed in phosphate buffered saline (PBS) and seeded into 24-well plates at a final concentration of 200,000 cells per well in 500 μl of antibiotic-free cMEM.…”

Section: Macrophage Infection Assaymentioning

confidence: 99%

“…In particular, IFN-γ and ceftazidime, an antibiotic used to treat melioidosis, both had individual effects in reducing bacterial burden from an in vitro macrophage infection model, but their combined effect resulted in synergistic reduction of bacterial burden [24,25]. This effect was shown both in vivo [25] as well as in vitro through the use of several macrophage cell lines [24], suggesting that therapies that combine immune stimulation with antibiotics may be promising strategies for treating melioidosis. Evidence suggested that IFN-γ-stimulated production of reactive oxygen species (ROS) contributed to the success of the combination therapy, as the effect of IFN-γ was reversed by a dose-dependent addition of the ROS-scavenging cellular antioxidants glutathione (GSH) and N-acetylcysteine (NAC), a precursor to GSH [24].…”

Section: Introductionmentioning

confidence: 99%

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Dietary antioxidant seleno-L-methionine protects macrophages infected with Burkholderia thailandensis

Pomposello¹,

Nemes²,

Mosovsky³

2020

PLoS ONE

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Burkholderia pseudomallei is a facultative intracellular pathogen and the causative agent of melioidosis, a potentially life-threatening disease endemic in Southeast Asia and Northern Australia. Treatment of melioidosis is a long and costly process and the pathogen is inherently resistant to several classes of antibiotics, therefore there is a need for new treatments that can help combat the pathogen. Previous work has shown that the combination of interferon-gamma, an immune system activator, and the antibiotic ceftazidime synergistically reduced the bacterial burden of RAW 264.7 macrophages that had been infected with either B. pseudomallei or Burkholderia thailandensis. The mechanism of the interaction was found to be partially dependent on interferon-gamma-induced production of reactive oxygen species inside the macrophages. To further confirm the role of reactive oxygen species in the effectiveness of the combination treatment, we investigated the impact of the antioxidant and reactive oxygen species scavenger, seleno-L-methionine, on intracellular and extracellular bacterial burden of the infected macrophages. In a dose-dependent manner, high concentrations of seleno-L-methionine (1000 μM) were protective towards infected macrophages, resulting in a reduction of bacteria, on its own, that exceeded the reduction caused by the antibiotic alone and rivaled the effect of ceftazidime and interferon-gamma combined. Seleno-L-methionine treatment also resulted in improved viability of infected macrophages compared to untreated controls. We show that the protective effect of seleno-L-methionine was partly due to its inhibition of bacterial growth. In summary, our study shows a role for high dose seleno-L-methionine to protect and treat macrophages infected with B. thailandensis.

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Cell free mitochondrial DNA in serum and milk associated with bovine mastitis: a pilot study

Leishangthem

Singh

et al. 2018

Vet Res Commun

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Mastitis is inflammation of mammary gland affecting all the species of domestic animals. Fragments of the mitochondrial genome released from dying cells are considered surrogate markers of mitochondrial injury. We hypothesized that bovine mastitis would be associated with increased cell free mitochondrial DNA (mtDNA) content in serum and milk. Milk and serum samples were collected from sub-clinical mastitic and normal animals. Mastitis was confirmed by California mastitis test and bacterial isolation. Oxidative stress, nitric oxide and inflammatory cytokines were also estimated. Real time polymerase chain reaction was conducted in serum and milk from sub-clinical mastitic animals and compared with healthy animals targeting the mtDNA genes cytochrome b. Mastitis animals showed higher oxidative stress markers and nitric oxide along with higher level of inflammatory cytokines. Cell free mtDNA was significantly higher in serum and milk of mastitic animals comparing to that of healthy control. The higher cell free relative mtDNA content in mastitis animals indicates injury to the mammary epithelial cells and thereby releasing the mtDNA in the milk and blood. This mtDNA may be a bio-marker of oxidative stress and tissue injury in bovine mastitis.

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

Cited by 11 publications

References 54 publications

IL-18 binding protein (IL-18BP) as a novel radiation countermeasure after radiation exposure in mice

IL-18 binding protein (IL-18BP) as a novel radiation countermeasure after radiation exposure in mice

Dietary antioxidant seleno-L-methionine protects macrophages infected with Burkholderia thailandensis

Cell free mitochondrial DNA in serum and milk associated with bovine mastitis: a pilot study

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