Multidrug-ResistantPseudomonas aeruginosaTriggers Differential Inflammatory Response in Patients With Endophthalmitis

Abstract

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.

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

“…While most studies focus almost exclusively on the virulence of the pathogen and the mode of action of the antibiotic, without explicitly considering the host immune response, few studies do suggest that the severity and outcome of an infectious disease is influenced by host-pathogen interactions ( 24 ). Analysis of human vitreous samples collected from different patients with endophthalmitis corroborated our in vitro observations of differential immune response ( 16 , 17 ). To further confirm this topological cluster of differential expression, we created an in vivo murine model of endophthalmitis for a comprehensive high-throughput gene expression profiling.…”

“…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.…”

“…Our previous studies also found similar overexpression of these IL-1β, IL-6, IL-10, and TNF-α cytokines in human microglial cells, retinal pigment epithelial cells, and human vitreous samples. Interestingly, IL-1α showed a differential expression in both in vitro and in vivo mice model infected with MDR-PA , but the same could not be corroborated in the human vitreous samples ( 16 , 17 ). This altercation might be due to the low human samples included in the study.…”

“…We have earlier reported an exacerbated immune 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 P. aeruginosa strains ( 16 ) as well as correlated this to levels in vitreous of patients with MDR- P. aeruginosa endophthalmitis ( 17 ), suggesting that MDR-PA infections have an excessive inflammatory response which affects restoration of vision. An adjunct approach through the use of immunomodulators that will regulate the expression of specific pathways or mediators, thus reducing ocular inflammation and restraining collateral damage is warranted.…”

Lipopolysaccharide enhances HSV-1 replication and inflammatory factor release in the ARPE-19 cells

“…In LPS-treated ARPE-19 cells, the levels of IL-6, IL-8, IL-18, TNF-α, IFN-γ and CCL2 also elevated ( Fernandez-Robredo et al., 2020 ; Qiu et al., 2021 ). These inflammatory factors were pro-inflammatory factors and involved in progressive retinal pathology, such as RPE degeneration and neovascularization ( Ijima et al., 2014 ; Leung et al., 2009 ; Li et al., 2009 ; Naik et al., 2021 ; Taghavi et al., 2019 ). TNF-α could induce RPE cells to migrate, which could be seen in the retina of HSV-1 infected mice ( Liu et al., 2012 ; Zheng and Atherton, 2005 ).…”