Meredith Gregory-Ksander

Dr. Meredith Gregory-Ksander received her PhD in cell biology from Loyola University Chicago in 1999 and joined the Schepens Eye Research Institute as a postdoctoral fellow with NIH support. In 2004, she was appointed Instructor in the Department of Ophthalmology at Harvard Medical School and Investigator at the Schepens. Soon after, she was awarded her first NEI-RO1 (independent researcher) grant; in 2006, she was appointed Assistant Scientist at the Schepens.

The eye is a complex organ where inflammation is tightly regulated to provide the eye with protection against pathogens, while at the same time protecting vision from sight-destroying inflammation. There are a variety of special mechanisms involved in regulating inflammation in the eye and together they are known as “immune privilege”. Meredith’s laboratory, in collaboration with Mike Gilmore’s, is working to unravel the mechanisms that regulate inflammation during infections of the eye. The ultimate goal is to develop novel therapies that enhance the host’s inflammatory response so that it eliminates the infection while reducing the destruction of normal eye tissue.

There are many different types of eye infections – viral, bacterial, fungal, and amoebic. These infections can affect different parts of the eye: (i) conjunctivitis is an infection of the conjunctiva (the clear membrane that covers the white part of the eye and the inner surface of the eyelids), (ii) keratitis is an infection of the cornea (the transparent front part of the eye that covers the iris and pupil), and (iii) endophthalmitis is an infection of the inside of the eye. Meredith’s lab focuses on bacterial endophthalmitis.

Normally, the inside of the eye is a sealed, sterile environment that is protected from the outside world. This is in contrast to the outside of the eye (for example, the conjunctiva), which is always in contact with bacteria. When an infection enters the inside of the eye, by way of either surgery or penetrating injury, it is called endophthalmitis. Because the tissues within the eye are very delicate, endophthalmitis is always serious and can lead to blindness and even to loss of the eye if not treated immediately. While infrequent, endophthalmitis is one of the most devastating eye complications that can occur following eye surgery. This type of infection occurs most commonly after cataract surgery, in approximately three out of 1000 patients. The cause of endophthalmitis is most often bacterial and the most common bacterial species are staphylococcus epidermis and staphylococcus aureus. The current treatment for bacterial endophthalmitis consists of early, aggressive dosage with a standard regimen of high-dose, broad-spectrum intraocular and systemic antibiotics. In severe cases, a vitrectomy is performed, in which the infected vitreous jelly within the eye is removed and replaced with a sterile saline solution. In some cases, corticosteroids are used to decrease inflammation and to speed healing. However, the use of corticosteroids is often debated, due to the double-edged nature of inflammation, as will now be discussed.

Inflammation is, on the one hand, beneficial and helps to get rid of (or “clear”) an infection; however, at the same time, inflammation can be detrimental, causing damage to uninfected tissue that results in a permanent scar. In tissues such as the skin, such a scar does not affect function.  However, a scar in the eye can lead to permanent loss of vision. Upon entry into the eye, bacteria incite an inflammatory response. A multitude of inflammatory products are released, resulting in increased recruitment of inflammatory cells to the site of the infection. Damage to the eye can occur from the breakdown of the inflammatory cells (which release digestive enzymes), as well as from the toxins produced by the bacteria.

Meredith’s laboratory predicts that the successful clearance of an infection requires: (i) quick identification of the invading bacteria, (ii) rapid recruitment and activation of inflammatory cells, and (iii) rapid turn-off of inflammation following bacterial clearance. The maximum amount of ocular tissue is destroyed when a “smoldering” inflammatory response clears the infection too slowly. A slow response also increases the risk that the infection will not be contained and will spread throughout the eye. Bacteria possess a variety of mechanisms they use to avoid and thwart inflammatory cells. When an infection is not cleared quickly, there is an increasing risk that the bacteria will successfully deploy these defenses and damage the retina.

Meredith’s laboratory is using a mouse model of staphylococcus aureus-induced endophthalmitis to examine the eye’s immune response to bacterial infections. She has identified two proteins – Fas ligand and aB-crystallin – that play a central role in regulating inflammation and protecting the host retinal tissue from destruction. Fas ligand is a protein that can be expressed both as a cell-membrane-bound protein that stimulates inflammation, and as a soluble protein that inhibits inflammation. Meredith’s work suggests that these different forms of Fas ligand work together to rapidly turn on inflammation (to clear the infection) and then to rapidly turn off inflammation (to prevent destruction of eye tissue). Alpha-B-crystallin works by a different mechanism: it is a small heat-shock protein that is expressed in the retina and is turned up during stressful situations, such as inflammation. Meredith’s work suggests that such upregulation of aB-crystallin in the retina protects the cells from destruction by preventing apoptosis (cell death). However, at the same time, the invading bacteria produce an enzyme that cleaves aB-crystallin, rendering this protein non-functional and unable to prevent cell death. Therefore, if cleavage of aB-crystallin could be blocked by a drug, retinal resistance to destructive endophthalmitis could be increased.

While the incidence of endophthalmitis after cataract surgery is rare, it has increased over the last decade. This rise is due, in part, to the increase in the 65-year and older population and the subsequent rise in the number of cataract surgeries being performed (about 2.5 million per year in the U.S.). Other factors include the emergence of antibiotic-resistant bacterial infections and changes in surgical technique. In addition, as new therapies evolve for the treatment of retinal diseases like age-related macular degeneration and diabetic retinopathy, involving the injection of drugs into the vitreous of the eye, the potential for endophthalmitis increases. Therefore, research on novel therapies that will replace and/or augment the use of antibiotics is needed. Furthermore, the ability to specifically turn inflammation on and off in the eye will be critical in preventing tissue destruction and preserving the maximum amount of vision following the successful treatment of an eye infection.