Einav Lab
Virus-Host Interactions - Bench to Bedside
Our basic research program focuses on understanding virus-host interactions in viral infection and disease pathogenesis. This program is combined with translational efforts to apply this knowledge toward the development of broad-spectrum, host-targeted antiviral strategies to combat acute emerging viral infections (e.g., flaviviruses (dengue, Zika); alphaviruses (equine encephalitis, chikungunya); coronaviruses; and filoviruses (Ebola, Marburg)) and predictive biomarkers for severe disease progression.
Our interdisciplinary studies focus on the following emerging concepts and approaches that are transforming our understanding of virus-host interactions and disease pathogenesis:
1. Understanding viral pathogenesis using an integrative, single-cell systems immunology approach.
Our goal is to elucidate the mechanisms that drive severe viral disease in distinct patient populations. To this end, our lab pioneered the development of viscRNA-seq (virus-inclusive single cell RNA-seq), which simultaneously quantifies viral RNA abundance and host transcriptional responses in individual cells from human samples. We integrate viscRNA-seq with complementary multi-omics approaches to study PBMC samples from our large Colombia dengue cohort (>600 patients) and our Zika microcephaly cohort, as well as arbovirus-infected tissues from cadavers and specialized human organoid models. These efforts are building a high-resolution atlas of viral cellular tropism and host responses across infected and bystander cell states and enabling identification of both protective and pathogenic programs. Our findings have already challenged prevailing paradigms, such as by characterizing hallmarks of severe dengue progression beyond the widely studied antibody-dependent enhancement mechanism, and by identifying B cells as the main target cells of dengue virus in the human blood versus the commonly reported myeloid cells. We have also applied this approach to elucidate mechanisms of tissue injury in COVID-19. Translationally, we aim to identify outcome-associated biomarkers and therapeutic targets and to inform vaccine strategies. For example, using a multicohort analysis framework in collaboration with the Khatri lab, we identified and validated a parsimonious (8-gene) signature that robustly predicts progression to severe dengue that is ready for clinical translation. Disciplines involved: Systems virology/immunology, bioinformatics, single cell transcriptomics, proteomics.
2. Deciphering intracellular membrane-trafficking pathways essential for viral replication.
We use integrated transcriptomic, proteomic, genetic, and pharmacological approaches to identify host factors required for replication of multiple globally important RNA viruses, including dengue virus, Zika virus, encephalitic alphaviruses, SARS-CoV-2, and Ebola virus. Our work dissects how RNA viruses hijack cellular membrane-trafficking pathways to execute key steps of the viral life cycle. We define the molecular mechanisms and cell-biological functions of these pathways—using viruses as powerful probes—across viral entry, genome replication, assembly, egress, and direct cell-to-cell spread. Current efforts focus on: (i) cellular kinases (NUMB-associated kinases, receptor tyrosine kinases, lipid kinases) and adaptor protein complexes that regulate viral trafficking; (ii) the ESCRT machinery in intracellular viral budding; and (iii) ubiquitin signaling networks that control trafficking during viral assembly and release.
Disciplines involved: Virology, cell biology, biochemistry, genomics, proteomics.
3. Advancing small molecules that target host functions as broad-spectrum antivirals with a high barrier to resistance.
Most current antivirals inhibit viral enzymes, yielding a “one drug, one virus” paradigm that is not scalable to meet the large unmet need and is often limited by viral resistance. We pursue an alternative strategy: host-targeted antivirals that inhibit cellular functions commonly hijacked by diverse viruses, offering broad-spectrum activity with a higher barrier to resistance. We have identified several host pathways exploited across RNA viruses, including NUMB-associated kinases (NAKs), ErbB receptor tyrosine kinases, and lipid kinases, as targets for broad-spectrum antiviral development. We have demonstrated the utility of repurposed approaches that inhibit these kinases in suppressing replication of multiple RNA viruses both in vitro and in mouse models with a high barrier to resistance. In parallel, we are developing chemically distinct small molecules targeting these cellular functions as both pharmacological tools to study cell biology and viral infection and as therapeutics to combat acute emerging viral infections. These studies provide proof of concepts that host-targeted antivirals can offer scalable, broad-spectrum solutions with a high barrier to resistance—diverting from the prevailing direct-acting antiviral paradigm. Notably, one of our kinase-targeted strategies was incorporated into a Gates Foundation–supported Ebola clinical trial protocol (NCT02380625), and additional programs are advancing toward interventions for dengue, COVID-19, and alphaviral disease.
Disciplines involved: Virology, cell biology, biochemistry, molecular pharmacology, medicinal chemistry, structural biology.
Taken together, in addition to a track record in innovative interdisciplinary basic research, our lab’s unique contribution is translating research findings to address major global health challenges.
