Bacterial Cloaking Devices in Intraocular Infections

About This Grant

PROJECT SUMMARY / ABSTRACT Bacterial eye infections cause a significant number of cases of blindness worldwide. Bacteria secrete an armamentarium of virulence factors that protect them from killing by immune cells. Most pathogens that infect the eye produce a polysaccharide capsule that covers the bacterial surface. This “cloaking” renders them invisible to receptors and pathways that would otherwise incite an immune response, protecting them from killing by immune cells. Unhindered growth results in virulence factor production. In the eye, this can manifest as an irreversibly damaged retina and significant vision loss. To make matters worse, many of these pathogens belong to the ESKAPE group (Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, Enterobacter) and are at the top of the CDC’s list of Antibiotic Resistance Threats in the US. Multidrug resistance is common in ocular isolates, elevating the risk of infections that are difficult to treat. Our program investigates the pathogenic mechanisms underlying ocular bacterial infections. For bacteria, animal infection models and ocular cell lines are used to investigate the areas noted above. We have a very good idea of the virulence factors that directly damage the retina and the innate pathways involved in inflammation. This proposal is focused on a common virulence factor which may be involved in cloaking bacteria during the earliest stages of endophthalmitis, events that, to date, have drawn minimal attention. This new R01 proposal is based on the overarching hypothesis that ocular pathogens are cloaked from the intraocular immune response by capsule expression in the eye during infection. The scientific premise is based on data demonstrating that: 1) capsule genes are expresssed in intraocular environments and in infected eyes of mice, 2) capsule-deficient mutants are not as virulent as bacteria that express capsule, 3) capsules are potential PAMPs and may interact with TLRs, and 4) anti-capsule antibody improves the clinical outcome of endophthalmitis caused by streptococci and non-ocular infections caused by encapsulated pathogens. These gaps are investigated in three separate but related aims focused on capsule-mediated cloaking of ocular pathogens in endophthalmitis. We will use well-characterized capsule-deficient mutants in in vitro and in vivo models in rigorous and straightforward experiments designed to define the role of capsule in endophthalmitis and the potential value of therapeutically targeting capsule to improve clinical outcome. For patients with eye infections, ineffective treatment often equates with vision loss. Our approach to addressing these gaps in our field are innovative, translationally relevant, and will move the ocular infectious disease field forward by focusing on a common bacterial virulence factor that is targeted in FDA-approved vaccines which have improved the health of millions. These studies are a logical extension of our ocular infection research program, and we are well positioned to contribute new and important information that will improve options for preventing infection and preserving vision.