Orthogonal Integration of Virus-host Interactions to Develop Broad-spectrum Antivirals

The picornavirus family contains various viruses that can cause different clinical manifestations, including common cold, hand-foot-and-mouth disease, herpangina, and acute hemorrhagic conjunctivitis. However, some of the picornaviruses cause severe neurological complications, including poliomyelitis, encephalitis, meningitis, myocarditis, and pulmonary edema, and even death. Although enterovirus A71 (EV-A71) vaccines have been licensed in China, developing vaccines against different picornaviruses remains a challenge. Therefore, broad-spectrum antivirals are warranted. The 4 specific aims of this project were to (1) search for common host factors involved in the replication of different picornaviruses, (2) integrate omics data and identify the mechanistic paradigm (linchpins) as targets for broad-spectrum antivirals, (3) establish a high-throughput screening assay and identify potential inhibitors, and (4) evaluate the functionality of inhibitors in newly established animal models. We identified several host factors required for the viral replication of coxsackievirus A6 (CV-A6), coxsackievirus A16 (CV-A16), EV-A71, enterovirus D68 (EV-D68), and coxsackievirus B3 (CV-B3) through CRISRP-Cas9 screening. We have validated the one of these candidates are critical in picornavirus replication. Moreover, we found a novel mechanism involved in picornavirus infection. In addition to enterovirus, this host factor is also involved in coronavirus, influenza A virus, and ZIKA virus infections. We further discovered that two FDA-approved drugs, which target to this host factor, could reduce the viral loads of enterovirus and coronavirus, including SARS-CoV-2. Therefore, we will further determine the effect of this host factor and its inhibitors on virus infection in mice model. In addition to CRISPR-Cas9 screening, and used the metabolic labeling method combine. We will further integrate data from CRISPR-Cas9 screening and the metabolic labeling method combined with the advanced proteomic analysis and next-generation sequencing to identify mechanistic paradigms (linchpins) as targets for broad-spectrum antivirals.

Project ID:PG11001-0112
External Project ID:NHRI-EX110-10833SI