Deciphering the novel role of casein kinase 1 alpha as a key regulator of Middle East respiratory syndrome coronavirus infection ​with quantitative phosphoproteomics

Dr Chan, Jasper Fuk Woo   (Principal Investigator (PI))

Dr Chu Hin   (Co-Investigator)

Dr Yuan Shuofeng   (Co-Investigator)

Professor Yuen Kwok Yung   (Co-Investigator)

Dr Sze Kong Hung   (Co-Investigator)

36

2021-01-01

1076894

Deciphering the novel role of casein kinase 1 alpha as a key regulator of Middle East respiratory syndrome coronavirus infection ​with quantitative phosphoproteomics

antiviral, casein kinase 1, coronavirus, MERS, phosphoproteomics

Infection/Parasitology,Clinical Microbiology

Biology and Medicine (M)

17124220

General Research Fund (GRF)

2020

On-going

1 Objective 1: To investigate the role of CSNK1A in MERS-CoV infection. Extending from our identification of CSNK1A as the most activated kinase in MERS-CoV-infected lung epithelial cells which affects virus replication, we will detailedly investigate its role in MERS-CoV infection in Objective 1. -Objective 1.1: To understand the biology of CSNK1A upon MERS-CoV infection: how the expression/activation of CSNK1A is modulated by MERS-CoV, cellular distribution of CSNK1A in MERS-CoV-infected cells, and the effect of CSNK1A overexpression on MERS-CoV replication. -Objective 1.2: To characterize the function of CSNK1A in MERS-CoV infection: MERS-CoV’s effects on different human-pathogenic CoVs in different cell types including human primary monocyte-derived macrophages and human primary small airway and bronchial/tracheal epithelial cells. -Objective 1.3: To dissect the mechanism of how CSNK1A affects MERS-CoV replication: the step(s) of the MERS-CoV replication cycle CSNK1A is involved in and the activating role of CSNK1A on substrate proteins that are involved in MERS-CoV replication. 2 Objective 2: To evaluate the effects of CSNK1A inhibitor as a novel treatment strategy for MERS-CoV infection. Our preliminary data showed that the CSNK1A inhibitor D4476 has in-vitro and in-vivo anti-MERS-CoV effects. In Objective 2, we will validate this finding and thoroughly assess the in-vitro, ex-vivo, and in-vivo anti-CoV effects of CSNK1A inhibitor. -Objective 2.1: To investigate the in-vitro antiviral activity of CSNK1A inhibitor against MERS-CoV and other human-pathogenic CoVs to determine if CSNK1A inhibitor may be a potentially ""pan-CoV"" antiviral. -Objective 2.2: To assess the anti-MERS-CoV activity of CSNK1A inhibitor in physiologically relevant ex-vivo culture systems, including ex-vivo human lung and kidney tissue cultures, and human intestinal organoids. - Objective 2.3: To evaluate the in-vivo activity and identify the optimal dosing regimen of CSNK1A inhibitor against MERS-CoV in a lethal hDPP4-knockin mouse model.