Yang Research Project Summary
Poxviruses remain to have significant impacts on the public health after the eradiation of smallpox, the deadliest disease in human history, as they comprise highly dangerous emerging and re-emerging pathogens of humans and other vertebrates. Poxviruses are also being utilized as vectors to treat various infectious diseases and multiple cancers. Like all viruses, poxviruses rely on host cell factors to complete their lifecycles. Consequently, there is a significant need to identify and characterize cellular functions required for poxvirus replication. However, the roles of most cellular functions in poxvirus replication are poorly understood. The objective of this project is to identify and characterize specific cellular functions that are important for poxvirus replication, using vaccinia virus as our model poxvirus. The approach is to first identify bioactives and chemical compounds with known cellular targets that inhibit vaccinia virus replication, followed by genetic and biochemical characterization to determine the underlying viral and cellular mechanisms. The project will be implemented through two parallel Specific Aims. In the Specific Aim 1, a class III protein deacetylase SIRT1 inhibitor Ex-527 has been identified to potently inhibit vaccinia virus replication in a small-scale screening. The viral and cellular mechanisms by which Ex-527 inhibition of vaccinia virus replication will be determined. Upon completion of this aim, it is anticipated to uncover the role of SIRT1 in VACV replication. In the Specific Aim 2, a high-throughput screening will be carried out to identify cellular functions important for vaccinia virus replication through screening a collection of bioactive and FDA-approved compounds. Upon accomplishing the aim 2, it is anticipated to understand the roles of cellular functions in vaccinia virus replication in a more comprehensive manner and to determine the most prominent candidates for follow-up mechanistic studies. Taken together, this project will provide novel insights into specific cellular functions in vaccinia virus replication through a chemical approach combined with genetic and biochemical characterization.