Wednesday, April 2, 2025
4/2/2025
Immunopathogenesis of Adenovirus Keratitis - PROJECT SUMMARY Conjunctivitis, a common ocular condition with a range of etiologies, is highly prevalent, affecting approximately 6 million people annually in the United States, accounting for 1% of all primary care office visits, and costing 430 million USD annually. Viruses are responsible for ~ 80% of conjunctivitis cases, and human adenoviruses (HAdVs) are implicated in up to 65%. A particularly severe variant of adenoviral conjunctivitis, epidemic keratoconjunctivitis (EKC) is caused principally by viruses within human adenovirus species D (HAdV-D), for example the highly virulent adenovirus type 37. The clinical manifestations of EKC include severe membranous conjunctivitis and epithelial keratitis, followed by delayed onset of multifocal subepithelial (stromal) corneal infiltrates that cause light sensitivity and reduced vision and can persist or recur for months to years after the acute infection. We have shown previously that acute HAdV-D infection of human keratocytes induces intracellular signaling and robust expression of neutrophil and monocyte chemokines, and that physical components of the adenovirus (viral capsid and DNA) initiate molecular pattern responses in the corneal stroma. However, why adenovirus keratitis can be chronic and recurrent when the infection has resolved and the adenovirus is no longer present has not been previously studied. The specific aims of this proposal are to test the hypotheses that 1) the post EKC cornea expresses a unique array of pro-inflammatory mediators, 2) the post EKC cornea retains innate immune cells with a chronically altered transcriptome, and 3) long- lasting pro-inflammatory changes in the post EKC cornea can be mitigated by epigenetic modifying agents. We will study the cornea in our adenovirus mouse keratitis model after resolution of the infection, using protein arrays and immuno-microscopy to elucidate the pro-inflammatory mediators responsible for chronic adenovirus keratitis, flow cytometry and single cell RNA-seq to determine infiltrating cellular phenotypes and individual cell type transcriptomes, and single cell ATAC-seq to determine changes in cellular chromatin of resident keratocytes and infiltrating cells. Finally, we will apply known modifying agents of cellular chromatin in an attempt to prevent, reduce, or reverse pro- inflammatory mediator expression and pathologic innate immune cell phenotypes in chronic adenovirus keratitis. These studies are designed to take us closer to our goal of effective information-based therapies against HAdV eye infections. EKC is a common affliction, and the proposed study addresses a major public health concern.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).