University of Turin, Italy
Student: Gloria Griffante, Ph.D. fellow
Supervisor: Prof. Santo Landolfo, M.D.
Co-Supervisor: Prof. Marco de Andrea
Human Cytomegalovirus (HCMV) is a widespread β-Herpesvirus carried by 70% up to 90% of the human population. Following primary infection, HCMV establishes a lifelong latency in cells of the myeloid lineage, where reactivation is often driven by inflammation. Autoimmune diseases (AD) are characterized by chronic inflammation due to an abnormal immune response against the body’s own tissue. In genetically predisposed patients, HCMV has been shown to be relevant in the pathogenesis of AD but whether it initiates or supports the development of AD is still not known. Citrullination is a post-translational modification (PTM) catalyzed by peptidyl arginine deiminases (PAD) that convert peptidylarginine into peptidylcitrulline, whose dysregulation has been associated with a spectrum of ADs, cancer, and neurodegenerative disorders.
In an effort to characterize post-translational modifications (PTMs) during HCMV infection, we came across an unprecedented mechanism of HCMV-induced citrullination (i.e. conversion of arginine into citrulline) of viral and cellular proteins. Accordingly, we found that inhibition of calcium-dependent protein arginine deiminase 2 (PAD2) ablates HCMV-mediated citrullination and virus growth.
Thus, we aim to test our central hypothesis that PAD2-mediated citrullination is a novel mechanism of host viral adaptation in HCMV-infected cells. The long-term goal for this project is to gain a complete understanding of citrullinome-mediated control of HCMV replication to develop targeted therapeutics for HCMV diseases and congenital human CMV infection.
Moreover these findings may shed light on the role of HCMV in the pathogenesis of ADs and provide possible medical interventions for their treatment.