Einav Lab Research Interests
Out goal is to better understand the roles of virus-host interactions in the viral lifecycle and pathogenesis and identify host functions required by multiple unrelated viruses. This program is combined with translational efforts to apply this knowledge for the development of broad-spectrum host-centered antiviral approaches to combat emerging viral infections. Our work has recently provided a proof of concept that effective host-centered broad-spectrum antivirals can be discovered and developed via repurposing. One such approach that emerged from our lab is advancing into clinic for the treatment of dengue and was selected for an “in drawer protocol” for future Ebola outbreaks. Another goal of our lab is to discover critical protective and pathogenic elements of the host response to dengue virus (DENV) and identify a robust set of genes predictive of severe dengue early in the course of infection.
Our work combines novel proteomic approaches, with molecular and systems virology, biochemistry, transcriptomic, genomic, cell biology, bioinformatics, immunology, medicinal chemistry and molecular pharmacology approaches to achieve these goals. We focus on hepatitis C virus (HCV), and several acute emerging viruses including DENV, Zika virus, Ebola virus (EBOV), and encephalitic alphaviruses. We utilize both in vitro and in vivo infection models of these viral pathogens either at Stanford or via collaborations.
The advantages of the host-targeted broad-spectrum
Global health is threatened by emerging viruses, such as dengue (DENV) and Ebola (EBOV), which largely lack effective vaccines or therapies. Most antiviral strategies targeting viral factors by “one drug, one bug” approaches are associated with the emergence of viral resistance and are developed slowly and expensively and therefore not easily scalable. Our goal is to overcome these challenges by developing host-targeted antiviral approaches.
1. Mechanisms by which RNA viruses hijack intracellular membrane trafficking pathways for mediating viral entry, assembly, release, and direct cell-to-cell spread. We have identified several sorting signals within Flaviviridae proteins that are involved in mediating key steps in the viral cycle. We are currently mapping the interaction networks of these signals with human proteins, and investigating the functional relevance, regulatory mechanisms, and inhibition of these interactions. Additional projects involve interactions with cytoskeleton dynamics proteins, ESCRT machinery, ubiquitin pathways and more.
2. Monitoring dynamics of immune responses and gene expression in the course of natural dengue infection. We have established a cohort of dengue patients in Colombia. We integrate innovative bioinformatics approaches with single-cell transcriptomics, and advanced immune monitoring technologies (e.g. CyTOF) to comprehensively analyze samples derived from this cohort. Our translational goal is to develop molecular prognostic tools for prediction of severe dengue infection prior to its onset.
3. Mapping the signaling pathways of cellular kinases essential for viral replication. We have discovered AAK1 and GAK, two host cell kinases, as novel targets for broad-spectrum antivirals. To better characterize the signal transduction that these poorly characterized kinases mediate, we have conducted high-throughput proteomic screens for identification of novel cellular phosphorylation targets of these kinases. We are currently validating these hits and defining their roles in normal state and viral infection.
4. Advancing the development of repurposed and novel, selective AAK1 and GAK inhibitors as broad-spectrum antivirals. We discovered that the combination of erlotinib and sunitinib, anticancer drugs with potent anti-AAK1 and GAK activity, has antiviral activity against multiple RNA viruses both in vitro and in mouse models. We are currently advancing this strategy into the clinic and studying its mechanism of action. In parallel, we have been developing chemically distinct, selective inhibitors of AAK1 and GAK and are currently optimizing these compounds to combat DENV and EBOV.
5. Mechanisms of HCV-related cancer. Chronic HCV infection is a major cause of hepatocellular carcinoma and is also associated with non-Hodgkin lymphoma. We study virus-host interactions involved in facilitating viral persistence (a precursor to HCV-related oncogenesis).