Viruses are experts at exploiting and manipulating the host in numerous and diverse ways to facilitate their lifecycle. Elucidating these viral mechanisms provides insight into the viral lifecycle and opportunities for therapeutic intervention. It also can provide insight into the host lifecycle, revealing cellular pathways that we did not know existed until viruses were found taking advantage of it. Using cutting edge imaging and spectroscopic technologies combined with novel lipidomic and proteomic approaches, our investigations have been at the forefront of understanding the virus-host interface, revealing novel replication and transmission mechanisms shared by many different human viruses.
Our investigations are broadly focused on understanding the role of membranes and specifically lipids, in the viral lifecycle. Many single positive strand and double strand RNA viruses, which include notable human pathogens such as poliovirus (PV), norovirus, hepatitis C virus, Dengue virus, rotavirus, exploit host intracellular membranes by assembling their replication machinery on the surface of these membranes. Even though these RNA viruses are profoundly different from one another in numerous important ways including capsid structure, infection mode, replication machinery, kinetics of replication, size of their genome, we discovered that remarkably many depend on the same lipids, such as phosphatidylinositol 4 phosphate and cholesterol to facilitate genome replication. We recently expanded our studies to investigate the role of membranes during viral release from cells and discovered an entirely new mode of viral exit and transmission process where many so-called non-enveloped viruses (i.e. those that consist of a naked capsid surrounding the genome), were released non-lytically from cells as populations of viral particles in membrane bound vesicles. We have found that intercellular transmission by populations of viral particles resulted in much greater infection efficiency then free viral particles, potentially a consequence of this novel mode of en masse transmission of genomes facilitating genetic cooperativity among multiple quasispecies of virus.
Our findings have opened up several new avenues of investigation, which we are currently pursuing. These include: determining the mechanisms by which lipids such as PI4P and cholesterol lipids modulate viral replication machinery; determining the role of vesicular transmission of viral populations on the activities of the immune system; and determining the role of this mode of transmission on viral genetic diversity and evolution. Our interdisciplinary studies span cell biology, virology and immunology and exploit cutting edge state of the art tools of microscopy, proteomics, lipidomics to address these questions.