Our lab focuses on the innate defense and immune regulatory mechanisms of the corneal epithelial cells. Epithelial tissue forms a protective lining of our body, including the outer surfaces that are exposed to the environment, as well as the inner body cavities, glands and ducts. It serves as an essential defense barrier stopping pathogens, both physically and chemically, right at the points of entry before they can cause diseases. We discovered that epithelial cytokeratin 6a (K6a) exerts a novel antimicrobial function via its glycine-rich C-terminal fragments. Our laboratory also discovered that K6a regulates signaling pathways that control production of inflammatory mediators. These are unexpected functions of keratin proteins since they have long been viewed as the building blocks of cytoskeleton that primarily maintain structural integrity and resilience of epithelial cells.Given the wide distribution of keratin 6a among different epithelial tissues, as well as the structural and functional similarities shared among different keratins, our studies aim to advance understanding of epithelial innate immunity and immunoregulation of the cornea and other sites of the body, and to contribute to new biocompatible anti-infective and anti-inflammatory strategies in the post-antibiotic era we are fast approaching.
Using corneal epithelial cell culture and conditional knockout mice in corneal infection and inflammation models, coupled with an array of modern proteomic, biochemical, cell biological and microscopic (fluorescence and live cell imaging) tools, our ongoing basic and translational research attempts to answer important questions including:
1. What are the mechanisms involved in fragmentation of cytokeratin 6a that produces its antimicrobial derivatives?
2. What are the mechanisms for regulating level of keratin fragmentation, as well as production, secretion and activity of keratin-derived antimicrobial peptides?
3. What are the mechanisms of K6a-mediated regulation of immune response?
4. Is keratin-based host defense and immunoregulation employed by multiple sites of the body besides the cornea? If these mechanisms are dysregulated, could it lead to increased disease susceptibility and severity?
4. Are synthetic keratin-derived antimicrobial peptides effective prophylactic and/or therapeutic agents against infection and inflammation of the cornea and other sites?
Karthikeyan Bose PhD
Jonathan Chan Ph.D.
1. Tam C, Mun JJ, Evans DJ, Fleiszig SM. (2012) Cytokeratins mediate epithelial innate defense through their antimicrobial properties. Journal of Clinical Investigation, 122(10):3665-3677. PMC3461926.
2. Lee JT, Wang G, Tam YT, Tam C. (2016) Membrane-active epithelial keratin 6a fragments (KAMPs) are unique human antimicrobial peptides with a non-αβ structure. Frontiers in Microbiology, 7:1799. PMC5105358.