Multidrug-Resistant Pseudomonas aeruginosa Evokes Differential Inflammatory Responses in Human Microglial and Retinal Pigment Epithelial Cells

Naik, Poonam; Singh, Sukhvinder; Vishwakarma, Sushma; Kaur, Inderjeet; Dave, Vivek Pravin; Kumar, Ashok; Joseph, Joveeta

doi:10.3390/microorganisms8050735

Cited by 9 publications

(15 citation statements)

References 46 publications

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“…Pathway analysis also concurred that the majority of the gene response in our study overlap with genes associated with inflammatory processes in the public database. The cytokine associations uncovered were however expected based on previous studies (16,17). Our previous studies also found similar overexpression of these IL-1b, IL-6, IL-10, and TNF-a cytokines in human microglial cells, retinal pigment epithelial cells, and human vitreous samples.…”

Section: Discussionsupporting

confidence: 81%

Transcriptomic and Histological Analysis of Exacerbated Immune Response in Multidrug-Resistant Pseudomonas aeruginosa in a Murine Model of Endophthalmitis

et al. 2022

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Multidrug-resistant (MDR) endophthalmitis is a serious threat to the whole spectrum of therapeutic procedures associated with the risk of managing and preventing vision loss. We have earlier shown the interplay of immune mediators in patients with MDR Pseudomonas aeruginosa (PA) endophthalmitis leading to worse outcome. Expanding on these findings, a murine model of endophthalmitis was developed to explore the effects of drug resistance on the pathogenesis by analyzing the temporal changes in retinal morphology along with its transcriptomic signatures. Clinical isolates of susceptible (S-PA) and multidrug-resistant PA (MDR-PA) were injected intravitreally in C57BL/6 mice followed by enucleation at 6 and 24 h time points postinfection. Disease progression and retinal changes were monitored by clinical and histological assessment and transcriptome analysis in a pair-wise manner. Histological assessment of MDR-PA eyeball revealed higher disease severity (p < 0.05), CD45+ cells (p = 0.007), MPO+ cells (p = 0.01), GFAP+ (p = 0.02), along with higher retinal cell death in mice infected with MDR-PA (p = 0.008). Temporal transcriptome analysis revealed differential expression of nearly 923 genes at 6 h p.i. and 2,220 genes at 24 h p.i. (FC ≥2, adjusted p-value <0.05). Pathway enrichment analysis identified differential regulation of chemokine- and cytokine-mediated, MAPK, and NF-кβ signaling pathways. In conclusion, rapid deterioration of retinal architecture and immune exacerbation was significantly associated with the MDR endophthalmitis, suggesting the need for immunomodulatory agents to strengthen host cell functions and support antibiotics to save the retinal structure from inevitable deterioration and restoration of the vision.

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Section: Discussionsupporting

confidence: 81%

Transcriptomic and Histological Analysis of Exacerbated Immune Response in Multidrug-Resistant Pseudomonas aeruginosa in a Murine Model of Endophthalmitis

et al. 2022

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“…The actions of these bacteria may depend on the structure of the bacterial cell wall components, which are recognized by different TLRs [ 44 , 45 ]. The MDR cell wall components activate distinct TLRs [ 46 , 47 ] that can result in the activation of additional signaling pathways, regulating not only cytokine production [ 43 , 48 ] but, for example, transcription factors that are involved in the regulation of iron metabolism as well, e.g., NRF2 that acts as a transcriptional regulator of both iron exporter ferroportin and the oxidative stress-induced protein heme oxygenase 1, which is also responsible for heme degradation [ 49 , 50 ]. Moreover, NRF2 can modify NFκB activity, which results in decreased cytokine production [ 50 , 51 , 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Distinct Effects of Escherichia coli,Pseudomonas aeruginosa and Staphylococcus aureus Cell Wall Component-Induced Inflammation on the Iron Metabolism of THP-1 Cells

Pandur

Tamási

Pap

et al. 2021

IJMS

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Macrophages are essential immune cells of the innate immune system. They participate in the development and regulation of inflammation. Macrophages play a fundamental role in fighting against bacterial infections by phagocytosis of bacteria, and they also have a specific role in immunomodulation by secreting pro-inflammatory cytokines. In bacterial infection, macrophages decrease the serum iron concentration by removing iron from the blood, acting as one of the most important regulatory cells of iron homeostasis. We examined whether the Gram-positive and Gram-negative cell wall components from various bacterial strains affect the cytokine production and iron transport, storage and utilization of THP-1 monocytes in different ways. We found that S. aureus lipoteichoic acid (LTA) was less effective in activating pro-inflammatory cytokine expression that may related to its effect on fractalkine production. LTA-treated cells increased iron uptake through divalent metal transporter-1, but did not elevate the expression of cytosolic and mitochondrial iron storage proteins, suggesting that the cells maintained iron efflux via the ferroportin iron exporter. E. coli and P. aeruginosa lipopolysaccharides (LPSs) acted similarly on THP-1 cells, but the rates of the alterations of the examined proteins were different. E. coli LPS was more effective in increasing the pro-inflammatory cytokine production, meanwhile it caused less dramatic alterations in iron metabolism. P. aeruginosa LPS-treated cells produced a smaller amount of pro-inflammatory cytokines, but caused remarkable elevation of both cytosolic and mitochondrial iron storage proteins and intracellular iron content compared to E. coli LPS. These results prove that LPS molecules from different bacterial sources alter diverse molecular mechanisms in macrophages that prepossess the outcome of the bacterial infection.

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“…NF-κB inhibition also increased the formation of autophagosomes, 35 a finding that correlates with our previous in vitro study where the MDR-PA burden was found to be higher than S-PA strain. 9 Interferon-stimulated genes and their association with STAT1 36 were investigated, and STAT1 overexpression was reported in cases of a drug-resistant TB strain. In Bacillus 11 and S. aureus 37 endophthalmitis, it has been shown that phosphorylation of STAT3 influences NF-кB activation and promotes the inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

“… 3 Considerable studies have shown that the severity of endophthalmitis is strongly correlated with intraocular inflammation, characterized by the infiltration of neutrophils and the production of inflammatory cytokines. 4 – 8 An earlier investigation by our group on retinal cells highlighted an exacerbated response of interleukin (IL)-6, IL-1α, IL-8, IL-10, IL-1β, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) in retinal and microglial cells exposed to MDR strains, 9 suggesting that MDR-PA infections have a more virulent behavior, and this excessive inflammatory response may hamper resolution of the infection.…”

Section: Introductionmentioning

confidence: 99%

“… 11 To date, several studies on severe pneumonia 12 – 14 and sepsis 15 , 16 have evaluated the inflammatory response; however, data regarding the inflammatory response in PA endophthalmitis are limited. 9 In fact, the issue has not been examined in human vitreous fluids, nor has the possible correlation of multidrug resistance with the ability of pathogens to elicit an immune response and subsequent induced inflammatory sequelae been assessed. Targeting the inflammatory pathways could be a viable immune-modulatory approach that might help in preserving the retinal function.…”

Section: Introductionmentioning

confidence: 99%

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Multidrug-ResistantPseudomonas aeruginosaTriggers Differential Inflammatory Response in Patients With Endophthalmitis

Naik

Singh

Rudraprasad

et al. 2021

Trans. Vis. Sci. Tech.

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Purpose Infections with multidrug-resistant Pseudomonas aeruginosa (MDR-PA) lead to poor clinical outcomes in endophthalmitis patients, and its interactions with the host immune system remain largely unknown. The current study aimed to determine the association of MDR-PA infection with the cytokine expression profile in patients with endophthalmitis. Methods Vitreous of 12 patients with culture-proven MDR-PA along with 12 samples from antibiotic-susceptible P. aeruginosa (S-PA) and 20 non-infectious controls were included in the study. Expression patterns of IL-6, IL-10, IL-1α, IL-1β, IFN-γ, TNF-α, IL-8, and GM-CSF in the vitreous were analyzed by multiplex immunoassay and correlated with the clinical severity. We also assessed the phosphorylation level of different immune pathway molecules. Results In the MDR-PA group, significantly ( P < 0.05) increased expression of IL-6, IL-8, IL-10, IL-1β, and TNF-α was observed in comparison with the S-PA group. The increased inflammatory mediators in MDR-PA correlated with the disease severity. Additionally, the increased expression of inflammatory mediators was positively correlated to the activation levels of Akt, STAT3, JNK, p70 S6 kinase, and NF-кB ( P < 0.05) in the MDR-PA group. Conclusions The current study shows the differential host immune response and phosphorylation levels of signaling molecules in MDR-PA endophthalmitis, thereby linking antibiotic resistance with distinct immune regulation. Translational Relevance This study provides evidence for the use of inflammatory mediator levels of IL-6, IL-8, IL-10, IL-1β, and TNF-α as potential diagnostic biomarkers of MDR endophthalmitis warranting prompt administration of immune modulators to avoid irreversible damage to the retina and vision loss.

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Multidrug-Resistant Pseudomonas aeruginosa Evokes Differential Inflammatory Responses in Human Microglial and Retinal Pigment Epithelial Cells

Cited by 9 publications

References 46 publications

Transcriptomic and Histological Analysis of Exacerbated Immune Response in Multidrug-Resistant Pseudomonas aeruginosa in a Murine Model of Endophthalmitis

Transcriptomic and Histological Analysis of Exacerbated Immune Response in Multidrug-Resistant Pseudomonas aeruginosa in a Murine Model of Endophthalmitis

Distinct Effects of Escherichia coli,Pseudomonas aeruginosa and Staphylococcus aureus Cell Wall Component-Induced Inflammation on the Iron Metabolism of THP-1 Cells

Multidrug-ResistantPseudomonas aeruginosaTriggers Differential Inflammatory Response in Patients With Endophthalmitis

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