Priscilla Yang, PhD
Assitant Professor
Department of Microbiology and Molecular Genetics, Harvard Medical School
Host response to viral infection and drug discovery: dengue virus, hepatitis B and C viruses
Investigate molecular mechanisms of dengue and hepatitis virus infection and replication; perform HTS for viral antagonists to identify host factors and pathways required for dengue virus infection and persistence.
Commercial Opportunities
Develop new therapies to combat dengue virus pathogenesis by employing customized high throughput screening techniques to identify small molecule compounds pharmacologically active against dengue virus infection and replication.
Dr. Yang’s lab mixes studies on the molecular mechanisms responsible for infection and propagation of particular viruses with robust small molecule screening and drug discovery efforts for small molecule viral antagonists. Recently published studies have demonstrated the lab’s success in screening for novel compounds that block dengue virus replication or assembly. The lab is well-positioned to extend these findings and delve more thoroughly into the role of host cell kinases, such as Src, that appear to be essential factors for successful dengue virus assembly within cells. The lab is now performing structure-function studies to elucidate the Src-dependant cellular processes usurped by dengue virus, and to improve the efficacy of small molecule Src inhibitors.
Current Research Interests
Dr. Yang’s laboratory is investigating the signal transduction pathways that intersect with the replication of pathogenic viruses, such as the dengue virus. The lab wants to build on this knowledge to develop novel therapies against dengue virus. These therapies may also be relevant for treating other pathogenic flavivirus infections. For example, it is extending its published work on the Src family tyrosine kinases to probe the hypothesis that protein kinase inhibitors may be effective for depressing viral titers in vivo.
Additionally, the Yang lab is interested in understanding the role of lipids in viral infection. Towards this end, they are using both analytical chemistry and cellular virology to probe the effects of viral infection on lipid metabolism and lipid-mediated signal transduction. In a recent global lipid metabolite profiling analysis, they observed that hepatitis B virus replication is associated with selective accumulation of 7-dehydrocholesterol, a penultimate intermediate of cholesterol biosynthesis. The dose-dependent association of HBV replication with steady-state levels of 7-dehydrocholesterol suggests that this sterol is biologically important to the virus and may highlight a new class of mechanisms by which viral pathogens perturb host biochemistry to favor their own propagation.
- Test protein kinase inhibitors as novel antagonists of dengue virus replication and assembly that may have therapeutic efficacy.
- Implement global screening methodologies to identify host pathways and proteins that support dengue virus replication, including chemical and RNAi screens.
Research Expertise
Dr. Yang has been investigating the changes to cellular biochemical equilibria that occur during infection by dengue virus as well as the hepatitis B and C viruses. These viruses are responsible for widespread human disease and are linked to the etiology of incurable diseases, such as hepatocellular carcinoma (the predominant form of liver cancer) and dengue hemorrhagic fever that have high mortality rates. The dearth of knowledge about intracellular events that support replication of these viruses has hampered drug discovery efforts. Moreover, studies on these viruses have historically been challenging due to the absence of suitable rodent models.
The lab has recently published important findings on cellular signaling mechanisms that are required for the replication of dengue virus. The lab combined biochemical analysis and high throughput screening using small molecule probes and RNA interference as part of that work. The high throughput assays were designed to identify known small molecule drugs and drug candidates that block dengue virus infection or replication within host cells. These findings implicated a subset of Src family kinases (SFK), a widely family of protein kinases widely studied in oncology and transplantation settings, as critical host factors required for the assembly of dengue virus virions. Thus, known drugs that block SFK activity may represent first-generation candidates that have utility for pharmacological intervention.
The antibody-based image assay configured for high throughput screening may also be valuable for identifying other potent antagonists of dengue virus. In addition, the dengue viral processes regulated by SFK may be conserved in other members of the Flavivirus family. Discovery and characterization of additional cellular kinases essential for dengue virus infection and replication are also active areas of investigation.