By Katarina A. Lewczyk | Date published: January 14, 2025

Megan Orzalli to Investigate Regulation of the NLRP1 Inflammasome by HSV-1  

Epithelial cells (keratinocytes) are the first cell type to be infected with HSV-1, but little is known about how this virus interacts with these cells.  

Megan Orzalli, PhD, assistant professor of medicine in the Division of Infectious Diseases and Immunology, has received R01 funding from the NIH’s National Institute of Allergy and Infectious Diseases to study how keratinocytes in the skin mount an innate immune response to herpes simplex virus 1 (HSV-1) and how this virus manipulates these cellular responses to productively infect its human host. In a recent publication featured in the Journal of Experimental Medicine, Dr. Orzalli demonstrated that HSV-1 activates an inflammatory cell death process in keratinocytes, mediated by a protein complex called the inflammasome. This cell death process would normally limit the ability of HSV-1 to successfully replicate and spread, but the virus employs a mechanism to block inflammasome function in these cells.  

Unexpectedly, Dr. Orzalli and her team found that a single viral protein was responsible for both activating and inhibiting the inflammasome in keratinocytes. With this funding, Dr. Orzalli and her colleagues will determine how this HSV-1-encoded protein triggers and inhibits inflammasome activation in keratinocytes. Completion of the study will provide insights into antiviral defense strategies that are active in human skin during the earliest stages of HSV-1 infection and may provide important targets for therapeutic intervention.