Virulence of Staphylococcus aureus Corneal Infections

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ABSTRACT Bacterial keratitis (corneal infection) is a vision threatening disease and contributes significantly to world blindness. The important human pathogen, Staphylococcus aureus, is a predominant cause of keratitis, causing aggressive infections that often lead to irreparable ocular tissue damage. While much attention has been given to understanding the pathogenesis of S. aureus in non-ocular sites of infection such as sepsis, endocarditis or osteomyelitis, surprisingly, relatively little is yet known about the bacterial virulence factors that govern S. aureus keratitis. In the absence of this knowledge, it is impossible to understand the fundamental pathogenesis of S. aureus keratitis or rationally design therapeutics to treat this blinding disease. Accordingly, the central goal of this proposal is to identify and characterize S. aureus genetic determinants that modulate keratitis. Given the unique environment of the ocular surface and cornea with respect to tear film composition, sheer forces generated from blinking, and relative immune privilege, we hypothesize that there will be a unique set of virulence factors that drive keratitis. Our laboratory has developed innovative tools that will allow, for the first time, the ability to prospectively identify and validate the comprehensive set of S. aureus virulence factors that play a role in BK pathogenesis. Our discovery pipeline leverages state of the art genomics and bioinformatics including whole genome sequencing, Tn-seq and RNA-seq to generate high priority leads for mechanism of action studies, as well as the evaluation of biologic significance in our murine model of keratitis. We have successfully used this approach to identify and validate enterotoxins, secreted bacterial proteins well known for their cytotoxicity and ability to modulate the host immune response, as important in mediating keratitis. Thus, this proposal will build on this exciting preliminary data to develop an expanded list of the key drivers of keratitis. Ultimately this work will directly advance our understanding of S. aureus keratitis pathogenesis and as such, may be foundational in supporting strategies for the therapeutic intervention of this debilitating disease.