Staphylococcus Biology in Ocular Infections

PROJECT SUMMARY / ABSTRACT
Bacterial eye infections cause a significant number of cases of blindness worldwide. Staphylococcus
aureus causes a majority of these infections of the cornea (keratitis) and interior of the eye (endophthal-
mitis). S. aureus produces several adhesins on its surface which aid in tissue attachment, surface components
which trigger innate immune pathways and inflammation, and toxins which disrupt barriers and kill immune
cells. The coordinated synthesis of these virulence factors aids the organism in host survival, and the host is
usually negatively affected. In the eye, this can manifest as a painfully damaged cornea or irreversibly
damaged retina, resulting in significant vision loss. To make matters worse, S. aureus is considered a Serious
Threat on the CDC’s list of Antibiotic Resistance Threats in the US. MRSA and multidrug resistance are now
common in ocular isolates, elevating the risk of ocular infections that are difficult to treat.
We and others have investigated the pathogenic mechanisms underlying ocular bacterial infections. For
S. aureus, animal infection models and ocular cell lines have been used to investigate the areas noted above.
We have a very good idea of which toxins damage the cornea and retina and which innate pathways are
involved in corneal and intraocular inflammation. This proposal is focused on the factors involved in the
earliest events in S. aureus ocular infections, events that, to date, have drawn minimal attention.
This new R01 proposal is based on the global hypothesis that coordinated regulation of S. aureus
adhesins and toxins facilitate adherence to tissue, barrier breach, and escape from the acute immune
response. The scientific premise is based on preliminary and published data demonstrating that: 1) adhesins
on the S. aureus surface, when absent, reduce adhesion to corneal cells, 2) leukotoxins, when absent, reduce
virulence in keratitis and endophthalmitis, and 3) S. aureus breach of the blood-retina barrier appears to be
adhesin- and toxin-mediated. These areas are investigated in three separate but related aims focused on early
events in S. aureus keratitis and endophthalmitis. We will use well-characterized S. aureus virulence factor-
defective mutants and feasible in vitro and in vivo infection models in rigorous and straightforward experiments
designed to define the S. aureus factors important in these events.
For patients with eye infections, ineffective treatment often equates with vision loss. Our approaches to
addressing these gaps in our field are innovative, translationally relevant, and will move the ocular infectious
disease field forward by identifying the S. aureus factors responsible for adhesion to tissue and circumvention
of the acute response, possibly uncovering targets that lead to more rational use or development of
therapeutics for prevention and treatment of infection. 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.

Grant Number: 5R01EY032073-05
NIH Institute/Center: NIH
Principal Investigator: Michelle Callegan