Chengjin Ye, PhD

The COVID-19 pandemic, caused by the virus SARS-CoV-2, has had a devastating impact on global health, especially lung health.  The virus continues to evade our defenses, causing breakthrough infections and long-term lung complications in many people. This research project focuses on a specific viral protein called NSP3, a key player in how SARS-CoV-2 infects cells and avoids our immune defenses. Our preliminary findings suggest that NSP3 acts as an enzyme to disable important immune signals, including interferons that play a crucial role in protecting the lungs from viruses. This research will help us understand how SARS-CoV-2 escape host limitations and establish infection. In the long term, this work will contribute to the American Lung Association’s mission to save lives by improving lung health and preventing lung disease.

Update: Our research focuses on the molecular interactions between SARS-CoV-2, the virus that causes COVID-19, and the human host during active infection. Using a novel reverse genetics system, we engineered a recombinant virus to "pull down" and identify critical protein-to-protein contacts. We discovered a pivotal interaction between the viral Nucleocapsid (N) protein and Nonstructural Protein 3 (NSP3). Our data reveals that NSP3 acts as a molecular saboteur, physically binding to and dephosphorylating IRF3. IRF3 is a key human protein required to trigger the "alarm" for the antiviral immune response and dephosphorylating it changes how cells turn signals off or change how they work. By silencing this signal, the virus effectively bypasses the body’s innate defenses. This discovery highlights NSP3 as a high-priority target for developing new antiviral therapies to restore natural immune recognition and combat COVID-19.