Abstract
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.
Highlights
Pseudomonas aeruginosa-associated endophthalmitis is often multidrug resistant [1, 2] causing fulminant intraocular infection with higher evisceration and enucleation rate [3,4,5] and loss of the eye itself
Our study presents the first in-depth analysis of differential immune pathogenesis in endophthalmitis caused by multidrug-resistant Pseudomonas aeruginosa compared with its antibiotic susceptible strain
Both histopathological and transcriptome analysis confirmed excessive expression of numerous immune mediators in MDR-Pseudomonas aeruginosa (PA)-infected male and female mice eyes leading to elevated retinal stress and retinal cell death and damage at a dose of 104 colony-forming units (CFU)/μl
Summary
Pseudomonas aeruginosa-associated endophthalmitis is often multidrug resistant [1, 2] causing fulminant intraocular infection with higher evisceration and enucleation rate [3,4,5] and loss of the eye itself. About 37% of patients required evisceration while 30.6% of the eyes progressed to phthisis bulbi, and only 14.5% of eyes had visual acuity better than 20/200 [7] This poor visual outcome despite treatment with second line of antibiotic warrants the need for alternative therapy in MDR-PA endophthalmitis. Several studies have characterized the role of altered host immune response involving cytokine regulation in MDR-tuberculosis infection and experimental pneumonia model [9,10,11] along with dysfunction of the Treg cells [12] and altered activation of cytotoxic CD8+ T cells [13], driving differential metabolic reprogramming [14]. FADD, Fas-associated protein with death domain; BCL2L15, B-cell lymphoma 2 like 15; TRAF6, TNF receptor-associated factor 6; TRAF1, TNF receptor-associated factor 1; TNFR2, TNF receptor 2; TNFRSF1A, Tumor necrosis factor receptor superfamily member 1A
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