Current Research and Scholarly Interests
Our basic research program focuses on understanding the roles of virus-host interactions in viral infection and disease pathogenesis via both molecular and systems virology/immunology single cell approaches. 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, including dengue, encephalitic alphaviruses, SARS-CoV-2 and Ebola, and means to predict disease progression.
Our interdisciplinary studies focus on the following emerging concepts that are transforming our understanding of virus-host interactions:
1. Understanding the pathogenesis of viral infections via an integrative systems immunology single cell approach. The goal of this project is to elucidate the cellular and molecular factors contributing to increased severity of viral infections e.g. dengue, Zika COVID-19 in distinct patient populations. To achieve this goal, we are advancing and utilizing various single-cell immunological approaches (virus-inclusive single cell RNA-seq, CyTOF etc), PBMC samples from our large Colombia dengue cohort (>500 patients) and Zika cohort, tissue samples from cadavers infected with arboviruses, as well as various unique human organoid models. We are mapping an atlas of viral immune cellular targets and studying critical protective and pathogenic elements of the host response to these viruses in multiple distinct infected and bystander cell subtypes with an unprecedented resolution. The translational goals of this project are to identify candidate biomarkers associated with infection outcome and candidate targets for antiviral therapy, as well as improve vaccine strategies. Notably, we have recently discovered such candidate biomarkers that are highly predictive of progression to severe dengue and are currently translating this discovery into the development of the first molecular prognostic assay to predict severe dengue early in the course of infection.
2. Deciphering the intracellular membrane trafficking pathways essential for viral pathogens. We use transcriptomic, proteomic, genetic, and pharmacological approaches to identify proteins that are critical for the replication of multiple globally relevant RNA viruses including dengue virus, Zika virus, encephalitis alphaviruses, SARS-CoV-2, hepatitis C virus, and Ebola virus. We are studying the molecular mechanisms by which these viruses hijack cellular membrane trafficking pathways for mediating key steps in their viral life cycle and are characterizing the roles these factors play in cellular biology using viruses as complexed probes. Ongoing work focuses on the roles of cellular kinases (NUMB-associated kinases, receptor tyrosine kinases, lipid kinases) and adaptor protein complexes in viral trafficking during various stages of the viral life cycle, the role of the ESCRT machinery in intracellular viral budding, and the roles of ubiquitin signaling pathways in the regulation of trafficking during viral assembly and release.
3. Advancing the development of small molecules targeting host functions as broad-spectrum antivirals. Most direct antiviral strategies targeting viral enzymes provide a “one drug, one bug” approach and are associated with the emergence of viral resistance. We have discovered several host functions exploited by multiple viruses as targets for broad-spectrum antivirals. We have demonstrated the utility of a repurposed approach that inhibits these factors in suppressing replication of multiple RNA viruses both in vitro and in mouse models, and are advancing this approach into the clinic and studying its mechanism of action. In parallel, we are developing chemically distinct small molecules targeting various cellular functions as pharmacological tools to study cell biology and viral infection and as broad-spectrum antivirals to combat SARS-CoV-2, dengue virus, encephalitic alphaviruses and Ebola virus.
