Tuesday, April 1, 2025
4/1/2025
Targeting Innate Inflammation Pathways to Treat Ocular Infections - PROJECT SUMMARY / ABSTRACT Endophthalmitis causes a significant number of cases of blindness worldwide. Efforts to prevent damage to delicate ocular tissues during infection rely on swift and proper use of therapeutics to rapidly kill organisms and arrest potentially damaging inflammation. Currently-used antibiotics can kill organisms, but the effective- ness of anti-inflammatory drugs is controversial. Because the intraocular inflammatory response during endophthalmitis can damage sensitive and nonregenerative retinal tissue, identifying more effective anti- inflammatory drugs which counteract or arrest these effects is critically needed. This new R21 proposal is based on the hypothesis that blocking the activity of innate immune pathways can protect the eye against the damaging effects of inflammation during bacterial endophthalmitis. The scientific premise of this work is based on: A) data highlighting the importance of innate immune pathway activation in the eye during experimental bacterial endophthalmitis, B) the presence of key proinflammatory mediators as an indicator of innate immune pathway activation in human and mouse eyes during bacterial endophthalmitis, and C) preliminary data demonstrating that genetic absence or therapeutic blockade of innate immune pathways arrests damaging inflammation in experimental bacterial endophthalmitis. We will test our hypothesis in experiments designed to determine the effectiveness of oxidized phospholipids with clinically-used antibiotics in limiting inflammation during experimental bacterial endophthalmitis. Our preliminary data demonstrates efficacy of an oxidized phospholipid (OxPAPC) in limiting inflammation caused by Bacillus, one of the most aggressive ocular pathogens. Because inflammation in endophthalmitis is driven by innate immune pathway activation, it is reasonable to posit that OxPAPC should limit inflammation caused by less aggressive pathogens. In addition to formulating a more effective strategy for Bacillus endophthalmitis by combining OxPAPC with clinically used antibiotics, we will test this strategy in endophthalmitis caused by S. aureus, a leading cause of multidrug-resistant (MDR) post-cataract surgical, intravitreal injection, and endogenous cases, as well as in Gram-negative endogenous endophthalmitis (EE) caused by the ESKAPE pathogen Klebsiella, to probe broad-spectrum usage. Defining the efficacy of OxPAPC in preventing ocular changes which preclude EE will provide additional data for this anti-inflammatory strategy. For endophthalmitis patients, ineffective treatment often equates with vision loss. Because inflammation is a significant component of pathogenesis, arresting this response is critical to protecting the eye. Our approach is novel for endophthalmitis, high-impact, translational, and will move the ocular infectious disease field forward by identifying a rational and more effective anti-inflammation strategy. These studies are a logical outgrowth of our research program, and we are ideally poised to contribute impactful information which will improve therapeutic options for preserving vision during ocular infections.
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