The role of iron in retinal degeneration during bacterial infection

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PROJECT SUMMARY When bacteria invade the eye, the resulting damage is rapid and irreversible. This type of infection, called endophthalmitis, is the most severe complication of intraocular surgery. Patient outcome is heavily dependent on the pathogenicity of the bacteria, its susceptibility to antibiotics, and the extent of inflammation. These factors can influence progression to the worst-case scenario, where the infected eye must be completely removed. Even in milder cases, some amount of permanent vision loss is common. Therefore, there is need for a treatment which targets both contributors to vision loss: bacterial growth and neurotoxic inflammation. All bacteria require iron for survival and proliferation. During infection, they must obtain iron from host tissues. In response, host cells will import iron to shield it from bacteria, initiating a competition for iron acquisition. However, iron accumulation within immune cells can promote inflammation. In animal models of diverse infections and diseases, iron chelation is both anti-bacterial and anti-inflammatory. My preliminary ex vivo data suggests that iron chelation inhibits bacterial growth in vitreous (fluid from within the eye), and that acute iron chelation is nontoxic to the retina. Aim 1 will expand on these results to determine the effectiveness of an iron chelator at preventing endophthalmitis in mice. I will examine the extent to which bacterial growth is inhibited and retinal structure is preserved over time. Although reducing bacteria would naturally reduce inflammation, the direct anti-inflammatory contribution of iron chelation would be unclear. Therefore, Aim 2 will investigate the link between iron accumulation and retinal inflammation. Using the murine endophthalmitis model, I will examine iron levels within retinal macrophages/microglia, and to what extent an iron chelator reduces retinal inflammation. The result will determine the anti-inflammatory potential of iron chelation treatment for endophthalmitis. The overall goal of this proposal is to prevent vision loss caused by bacterial infection.