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 retinal tissue, identifying more effective anti-inflammatory drugs which counteract or arrest these effects is critically needed. This revised R21 proposal is based on the hypothesis that blocking the activity of proinflammatory mediators can protect the eye against the damaging effects of inflammation during bacterial endophthalmitis. The scientific premise of this work is based on: A) the presence of mediators CXCL1/8, CCL2, and CXCL10 in the eye during experimental mouse and human bacterial endophthalmitis, B) preliminary data demonstrating that in Bacillus endophthalmitis: (1) CXCL1 is a key mediator of inflammation, (2) CXCL1 expression is augmented in the absence of other proinflammatory mediators, (3) absence of CXCL1 limits intraocular inflammation (also seen in S. aureus endophthalmitis), and (4) intravitreal anti-CXCL1 limits intraocular inflammation, and C) the absence of CCL2 or CXCL10 results in significantly less intraocular inflammation. We will test our hypothesis in experiments designed to determine the effectiveness of anti-CXCL1 with antibiotics, as well as the potential role of CCL2 and CXCL10 in inflammation during experimental bacterial endophthalmitis. Our preliminary results demonstrated efficacy of anti-CXCL1 in limiting inflammation caused by Bacillus, one of the most aggressive ocular pathogens. It is reasonable to posit that anti-CXCL1 should limit inflammation in endophthalmitis caused by less aggressive pathogens. In addition to formulating an effective strategy for Bacillus by combining anti-CXCL1 with clinically used antibiotics, we will test this strategy in endophthalmitis caused by Staphylococcus aureus, a leading cause of severe post-cataract surgical, intravitreal injection, and endogenous cases. Further, defining the importance of other proinflammatory mediators in this disease will provide additional targets on which to test combination strategies. For endophthalmitis patients, ineffective treatment often equates with vision loss. Because inflammation is a significant component of pathogenesis, identifying agents which arrest this response is critical to successful therapy. Our approach is novel for endophthalmitis, high-impact, translationally relevant, and will move the ocular infectious disease field forward by identifying a rational and more effective anti-inflammation strategy. The proposed studies are a logical outgrowth of our ocular infection research program, and we are well positioned to contribute new and valuable information which will improve the therapeutic options in preserving vision during ocular infections.

R21EY028066

2019-01-01

2021-12-31