Abstract
Purpose :
Recently, we performed global metabolomics and transcriptomic analyses to determine key signaling pathways perturbed during experimental S. aureus endophthalmitis. We observed dysregulation in purine metabolism with a significant decline in “adenosine” levels. Here, we sought to determine the role of adenosine signaling in the pathobiology of bacterial endophthalmitis.
Methods :
Bacterial endophthalmitis was induced in C57BL/6 mice by intravitreal (IVT) injection of S. aureus (SA) strain, RN6390. Retinal tissue was used for metabolomics and transcriptomic studies. The physiological role of adenosine was determined by IVT injection 6 h post-SA infection. Disease progression was evaluated by a daily eye exam and ERG analysis and assessment of bacterial burden and inflammatory cytokines. Mechanistic studies were performed using cultured human retinal Müller glia, mouse bone marrow-derived macrophages (BMDMs), and challenging them with S. aureus in the presence/absence of adenosine or specific inhibitors/activators.
Results :
Our temporal metabolomics and transcriptomic analyses revealed a time-dependent decrease in adenosine levels and its signaling pathway genes in S. aureus-infected mouse retina. Interestingly, intravitreal administration of adenosine significantly reduced bacterial burden and intraocular inflammation resulting in preserved retinal functions. The supplementation of adenosine enhanced the expression of its signaling pathway genes CD73 and ADORA1. Moreover, adenosine treatment enhanced the expression of antimicrobial peptides viz. S100A7/A8 in Muller glia and BMDMs, resulting in increased bacterial phagocytosis and killing. Adenosine treatment exhibited anti-inflammatory properties in SA-infected cells.
Conclusions :
Our study demonstrates reduced adenosine and impairment of its downstream signaling during bacterial endophthalmitis. Adenosine derivatives could be used as an anti-inflammatory/anti-bacterial therapy to improve visual outcomes in endophthalmitis.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.