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OHSU Finds Pathway Herpes Uses To Trigger Eye Disease

Study shows virus originating in the cornea can trigger herpes stromal keratitis.

Oregon Health & Science University researchers have demonstrated that herpes simplex virus persistent or latent in the eye can trigger the most common infectious cause of blindness.

 In a study published recently in the Proceedings of the National Academy of Sciences, OHSU investigators demonstrated the herpes virus does not require a round trip from the cornea into the nervous system and back to the cornea to cause the recurrent inflammatory disease known as herpes stromal keratitis, or HSK. The dogma among scientists and ophthalmologists has been that virus originating from sensory neurons, where the virus is latent, is required to cause HSK in the cornea.

 Instead, the researchers found that the herpes virus that remains latent or persistent in the cornea is sufficient for the disease. The virus likely travels the short distance from the cornea's top layer, the epithelium, where infection begins, to a deeper layer of the cornea, the stroma, where inflammation and disease ensues, said study co-author David Johnson, Ph.D., professor of molecular microbiology and immunology, OHSU School of Medicine. The results are consistent with observations that the herpes virus often is found in corneas removed for transplantation.

 To test the notion that HSK can occur without this round trip into the nervous system, Johnson's team created a herpes mutant lacking US9, a membrane protein that promotes virus movement in neuronal axons, the tiny connections between the nerve cell body and the tissue surface. This mutant could replicate normally in the cornea and could move into neurons, but it could not return to the cornea.

 Johnson's group found that the mutant virus was able to cause HSK just as well as normal herpes virus. "Thus, virus that remains in the cornea, either in a persistent or latent state, is capable of causing the disease without a round-trip into the nervous system," Johnson concluded. "However, this is not to say that virus latent in neurons does not also contribute to disease."

 According to the National Institutes of Health's National Eye Institute, about 400,000 Americans experience herpes virus infections in the eye and nearly 50,000 new or recurring cases are diagnosed each year. Herpes virus is the most frequent infectious cause of blindness in the U.S. HSK is an inflammatory disease, caused by the body's own immune system infiltrating the corneal stroma to rid the tissue of virus. However, immune responses often go wrong, becoming overblown and instead more broadly attack corneal cells, causing scarring of the cornea, which may eventually lead to vision loss and blindness.

 Since herpes virus can remain latent in neurons, scientists thought that recurrent infections in neurons lead to repeated reinfection of the cornea and inflammation which, over time, leads to progressive scarring of the cornea. Observations that herpes virus present in the cornea itself can lead to keratitis may cause clinicians to rethink the paradigm of infection, latency and reinfection.

 Herpes virus can be a major problem in patients undergoing corneal transplantation. Virus persistent or latent in the transplanted cornea can infect the recipients, leading to HSK in some patients. Johnson noted that, "Again, these cases of transfer of HSV from donor to recipient support the notion that there is HSV latent, or quiescent, in the cornea."

 Corneal transplantation and HSK are relatively rare diseases, but simple corneal surgeries to correct more minor defects in sight, such as LASIK, are becoming common. In rare instances, these surgeries can lead to reactivation of herpes virus in the cornea and damage to vision. Antiviral drugs that block herpes replication as well as anti-inflammatory steroids are available to treat HSK in most patients. However, better drugs and treatment methods are needed, and the OHSU research may help point efforts in this direction.

 In addition to Johnson, the paper was co-authored by Katarina Polcicova, who did this work as part of her Ph.D. studies at OHSU and who has recently returned to the Slovak Academy of Sciences, Bratislava, Slovakia, and by Todd Wisner, a research associate at OHSU. Barry Rouse, Ph.D., D.Sc., and his colleagues at the University of Tennessee's College of Veterinary Medicine also were collaborators.

 The study was funded by the National Eye and National Allergy and Infectious Diseases institutes.


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