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Postdoc Sukhvinder Singh, Ph.D., left, and Associate Professor Ashok Kumar, Ph.D.
Researchers at Wayne State University Medical School have found that a metabolite called itaconate, which is produced during cell metabolism, plays a role in protecting the eye from abnormal inflammation during infection. The metabolite can be used with antibiotics to treat eye infections.
A metabolite is a substance that is formed in or as an end result of metabolism.
The study was led by Ashok Kumar, Ph.D., an associate professor in the Department of Ophthalmology, Visual and Anatomical Sciences, and the Kresge Eye Institute.
The results “Integrative Metabolomics and Transcriptomics Identify Itaconate as Add-On Therapy for the Treatment of Bacterial Eye Infections” are published in the May issue of Cell Reports Medicine, a Cell Press journal.
Itaconate is naturally produced by the host’s innate immune cells to reduce inflammation and is not immunosuppressive. This makes it an ideal adjunct therapy for controlling excessive inflammation in the eye.
“This therapeutic strategy is likely to improve visual outcome in patients with bacterial endophthalmitis, where antibiotics kill bacteria and itaconate reduces excessive inflammation. Since some recent studies have shown the possible use of itaconate to downregulate inflammation in COVID-19, more research is being conducted in our laboratory to assess the effects of itaconate on SARS-CoV-2 and other RNA viruses such as Zika, Dengue, and Chikungunya to determine. ” he said.
His laboratory studies how various insects such as bacteria, viruses, and fungi cause eye infections, and is working to discover new therapies to prevent or treat them.
“Eyes are incredibly resistant to infection. However, eye surgeries such as cataracts or vitrectomy often predispose people to developing an infection. As the aging population increases worldwide, the demand for eye surgeries increases, leading to a proportionally higher incidence of post-operative infections, ”said Dr. Kumar.
Bacterial endophthalmitis is one of the most common infections after eye surgery when bacteria gain access to the inside of the eye from outside the eye such as the eyelid, conjunctiva, or other surfaces. “The first event that occurs when bacteria enter the eye is induction of inflammation, the body’s natural defense system to fight infection,” he added.
Patients with bacterial endophthalmitis often experience pain, redness, and blurred vision due to the mobilization of an arsenal of cells and molecules in the eye. While the response is essential to contain an infection, it often derails and damages the tissues in the eye, resulting in partial or total loss of vision. Current management of bacterial endophthalmitis includes local or systemic antibiotic therapy that is highly effective in killing the insects but does little to reduce inflammation. The ideal treatment should target both.
Researchers used animal and cell culture-based models to study the pathobiology of endophthalmitis, which is caused by a variety of bacterial and fungal pathogens.
“In this study, we decided to use high-throughput transcriptomics and metabolomics to visualize global changes in genes and metabolites during an infection of the eye. These newer technologies are increasingly being used to uncover disease mechanisms and biomarkers, and we have used them in the past, ”said Dr. Sukhvinder Singh, postdoctoral fellow in Dr. Kumar’s lab and lead author of the study. “When we integrated our metabolomics and transcriptome data, we received information about important gene and metabolic pathways that have been altered in the retinal tissue of bacterially infected mouse eyes. Among various metabolites and genes, we observed a strong correlation between the expression of a gene called immunoreactive gene 1 (Irg-1) and the production of a Kreb cycle metabolite called itaconate. Since itaconate was shown to be produced by immune cells, we tried to investigate its role in the eye, which was not known. “
The observation was made in the animal model, but the researchers asked if the changes also occur in human endophthalmitis. To find an answer, Dr. Kumar to longtime associate Joveeta Joseph, Ph.D., a senior scientist and microbiologist at the LV Prasad Eye Institute in Hyderabad, India. Dr. Joseph has a large biobank of vitreous samples from endophthalmitis patients.
“During their assessment, it was surprisingly found that the itaconate levels in the vitreous humor of the endophthalmitis eyes were increased. This observation further supported our discovery in the mouse model and its translatability to diseases of the human eye, ”said Dr. Kumar.
They are also reviewing its applicability in the inflammatory eye disease uveitis, which is now being treated with steroids. The immunosuppressive nature of steroids could cause harm in microbial infections, he said.
The study was supported by the National Institutes of Health with grants R01EY026964, EY027381, and R21AI140033.