Lipid Droplet-Enriched Luminogens Enable Adoptive Macrophage Transfer for Treatment of Bacterial Sepsis
Ontology highlight
ABSTRACT:
ORGANISM(S): Staphylococcus aureus
PROVIDER: GSE289543 | GEO | 2025/05/01
REPOSITORIES: GEO
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Project description:A leading cause of morbidity and mortality during influenza infection is the development of a secondary bacterial pneumonia, which is appropriately treated with antibiotics. In the absence of a bacterial superinfection, prescribing antibiotics is not indicated but has nevertheless become a common clinical practice for those presenting with a respiratory viral illness. We found that antibiotic use during an antecedent influenza infection impaired the lung innate immunologic defenses toward a secondary challenge with methicillin-resistantStaphylococcus aureus(MRSA). The antibiotics perturbed the gut microbiome causing a fungal dysbiosis that drives an increase in lung eosinophils. We also demonstrate eosinophils, through the release of major basic protein, impair macrophage ability to clear MRSA. Moreover, we provide clinical evidence that eosinophils positively correlate with antibiotic use and worsened outcomes in patients hospitalized for viral infections. Altogether, our work establishes a counterproductive effect of antibiotic treatment during influenza infection that have negative immunologic consequences in the lungs thereby increasing the risk of developing a secondary bacterial infection.
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Project description:Deeper understanding of antibiotic-induced physiological responses is critical to identifying means for enhancing our current antibiotic arsenal. Bactericidal antibiotics with diverse targets have been hypothesized to kill bacteria, in part, by inducing production of damaging reactive species. This notion has been supported by many groups, but recently challenged. Here we robustly test the hypothesis using biochemical, enzymatic and biophysical assays along with genetic and phenotypic experiments. We first used a novel intracellular hydrogen peroxide (H2O2) sensor, together with a chemically diverse panel of fluorescent dyes sensitive to an array of reactive species, to demonstrate that antibiotics broadly induce redox stress. Subsequent gene expression analyses reveal that complex antibiotic-induced oxidative stress responses are distinct from canonical responses generated by supra-physiological levels of H2O2. We next developed a method to dynamically quantify cellular respiration and found that bactericidal antibiotics elevate oxygen consumption, indicating significant alterations to bacterial redox physiology. We further show that catalase or DNA mismatch repair enzyme overexpression, as well as antioxidant pre-treatment limit antibiotic lethality, indicating that reactive oxygen species causatively contribute to antibiotic killing. Critically, the killing efficacy of antibiotics was diminished under strict anaerobic conditions, but could be enhanced by exposure to molecular oxygen or addition of alternative electron acceptors, suggesting that environmental factors play a role in killing cells physiologically primed for death. This work provides direct evidence that bactericidal antibiotics, downstream of their target-specific interactions, induce complex redox alterations that contribute to cellular damage and death, thus supporting an evolving, expanded model of antibiotic lethality. Here, we used microarrays to analyze oxidative stress responses to bactericidal antibiotic treatment in wildtype and mutant E coli WT or mutant E coli cells were grown to OD ~0.3. Untreated cells were harvested at time 0 as controls. Treated cells given the appropriate chemical perturbation and harvested 1 hour post-treatment. All experiments were performed in technical triplicate.
2014-04-02 | E-GEOD-56133 | biostudies-arrayexpress
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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is a major threat to human health, as the US mortality rate outweighs those from HIV, tuberculosis, and viral hepatitis combined. In the wake of the COVID-19 pandemic, antibiotic resistant bacterial infections acquired during hospital stays have increased. Instead of designing and deploying new antibiotics which MRSA would quickly develop resistance to, adjuvants are a key strategy to combatting these bacteria. We have evaluated several small molecule adjuvants that have strong potentiation with β-lactam antibiotics and have now investigated at the molecular level how the lead adjuvant exerts its effects. We hypothesized that the expression levels of key resistance genes would decrease once cotreated with a β-lactam antibiotic (oxacillin) and the adjuvant (compound 8). Furthermore, bioinformatic analyses would reveal biochemical pathways enriched in differentially expressed genes. RNA-seq analysis showed 176 and 233 genes significantly up and downregulated, respectively, upon cotreatment with oxacillin and compound 8. We identified four subclusters of genes that were regulated in similar patterns in response to drug treatment. Many of these genes displayed a similar pattern of expression where they were unaffected by compound 8 treatment alone, upregulated upon antibiotic challenge, and downregulated again upon cotreatment. GO categories that were significantly enriched among downregulated genes involved carbohydrate utilization and/or transport. Most of the biochemical pathways enriched with significantly downregulated genes involved carbohydrate utilization, such as the citric acid cycle (p=6.4x10-6) and the phosphotransferase system (p=1.8x10-5). The most populated pathway was S. aureus infection (p=3.0x10-3). Creating a network of affected gene products helped uncover potential master regulators for further investigation. This study revealed a dramatic impact of our lead adjuvant on the transcriptome that is consistent with a pleiotropic effect. These results point to this adjuvant as having potential broad therapeutic use in combatting MRSA infections.
2022-04-14 | GSE193395 | GEO
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