Multiple Receptor Tyrosine Kinases Regulate Dengue Infection of Hepatocytes

Abstract

Currently, there is no way to constrain dengue virus (DENV) infections in the clinic. My dissertation work explored the hypothesis that host kinase regulators of DENV infection have the potential to be therapeutically disrupted. I performed a thorough review of literature on host factors regulating dengue and summarized the growing body of evidence supporting kinase-targeted interventions for DENV infection and disease. I also conducted experimental work to elucidate kinases regulating DENV infection that can be targeted by existing drugs. Specifically, I performed kinase regression (KiR), an innovative tool that predicts kinase regulators of infection using existing drug-target information and a small drug screen. From this, thirty-six kinases were predicted to have a functional role in DENV infection. I investigated the role of the predicted receptor tyrosine kinases (RTKs) – EPH receptor A4 (EPHA4), EPH receptor B3 (EPHB3), EPH receptor B4 (EPHB4), erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 2 (FGFR2), Insulin like growth factor 1 receptor (IGF1R), and ret proto-oncogene (RET) – because there is already an existing repertoire of drugs against RTKs in the clinic. I found that predicted RTKs are expressed at higher levels in DENV infected cells, and that the activity of ERBB2 and IGF1R is induced following infection. I also demonstrated that knockdown of ERBB2, FGFR2 and IGF1R reduces DENV infection in some cases. I discuss therapeutic strategies that my work suggests could block dengue infection in the clinic and highlight further research that should be done to bolster these strategies. In addition to my primary dissertation research, I collaborated with colleagues to publish a research article uncovering how DENV interacts with mammalian target of rapamycin (MTOR) to support infection, as well as a review article highlighting how identification of host regulators across viral infections, malaria, and cancer have informed therapeutic strategies.