Title : Innate receptor PGLYRP2 is a functional sensor and hepatic scavenger for hepatitis B virus

Abstract:

The stealth property of Hepatitis B virus (HBV) has been questioned. The hepatic immunocompetence and effective innate immune responses are necessary for spontaneous clearance of HBV infection, however, the underlying mechanisms remain unclear. Here we observed a negative correlation between the expression level of hepatocyte-specific innate sensor Peptidoglycan Recognition Protein 2 (PGLYRP2) and HBV infection status in HBV-infected human liver tissues (p<0.001), and demonstrated that PGLYRP2 with an age-related expression pattern inhibits viral replication by binding to HBV Core/Enhancer II promoter through its PGLYRP2^209-377 domain, as well as enhances viral clearance by interacting with HBV capsid.

The direct interaction between PGLYRP2 and HBV capsid triggers nucleocytoplasmic translocation of PGLYRP2, and enhances secretion of the capsid-associated PGLYRP2, which subsequently activate immune effector cells. Conversely, loss of PGLYRP2 compromises HBV control in hepatocytes.

This study identifies a novel mechanism of interaction between HBV and innate immunity, in which PGLYRP2 exerts its function through direct-acting inhibition of HBV replication, acceleration of HBV core protein-targeting viral clearance, and modulation of hepatic microenvironment, thereby contributing to the recognition and spontaneous HBV clearance.

Audience Take Away:

• Despite breakthrough in discovery of NTCP as host cell entry receptor of HBV, the functional HBV sensor and scavenger that related with the pathophysiological mechanism of spontaneous HBV clearance have not been identified.
• Most HBV-infected infants cannot achieve spontaneous viral clearance compared to infected adults, indicating that the age-related hepatic immunocompetence and effective immune response contribute to spontaneous HBV clearance.
• A better understanding of how immune-competent hepatocytes spontaneously clear HBV infection may present new opportunities to achieve effective control and functional cure of HBV infection.
• Hepatic innate sensor PGLYRP2 can achieve spontaneous HBV clearance in combination with its direct-acting antiviral and immunomodulatory activities, which supports that the ability of the innate immunity to sense and react to HBV.
• Development of novel strategies for augmenting PGLYRP2-induced antiviral activity may provide an effective therapeutic intervention against chronic HBV infection.

Biography:

Dr. Shi studied Biomedical engineering at the Harbin Institute of Technology (HIT), Harbin, and entered joint Ph.D. program with Texas A&M Health Science Center, Houston in 2009. He received his PhD degree in 2014. After one and half year’s postdoctoral fellowship supervised by Dr Hao Wu at the Boston Children’s Hospital, Harvard Medical School, USA. He obtained the position of an Associate Professor at the HIT. The Shi laboratory of mechanistic immunology focuses on elucidating the molecular and cellular mechanisms that govern the regulation and therapeutic intervention of pattern recognition receptors in innate immunity. Our current research focuses on investigating the mechanisms of inflammation in infectious disease and tumorigenesis, especially the inflammation induced by innate immune signaling.