Molecular basis of Influenza A virus strains specific virulence and pathogenesis

Influenza A viruses manifest a range of disease severity in humans, depending on the viral strains. We hypothesize that IAV strains differ in their interaction with host cellular factors, which results in variable disease outcome. To understand the molecular basis of IAV strain specific virulence and pathogenesis, we are applying genome wide CRISPR-Cas9 screening platform using reporter-IAV strains to study strains specific host interactions. We’ve long term interest in applying CRISPR-Cas screening platforms to study virus-host interactions, antiviral innate immunity and molecular basis of viral pathogenesis of Flaviviruses such as Zika and Dengue.

Development of novel influenza vaccines for broad spectrum and long lasting protection

Influenza viruses are moving targets, constantly acquiring genetic changes which allow escape from host immunity. This is why a new vaccine needs to be formulated every year, and often it doesn’t provide the protection against the circulating influenza, as virus has already drifted. Also current vaccines primarily use viral components which generate antibody response. In order to provide broad protection we are trying to combine conserved components of viral proteins which illicit both humoral and cellular immunity, and potentiating this response through novel adjuvants.

Study of Influenza A virus life cycle events and requirements by live imaging

We have developed a novel replication competent IAV which allows live visualization of IAV structural protein Hemagglutinin in infected cells. This will be used in high resolution live imaging, to study cellular factors, HA posttranslational modifications which are required for IAV HA synthesis, trafficking, virion morphogenesis and budding events. In addition this tool allows production of fluorescent virus particles and will be used to study factors required for IAV entry and HA fusion in endosomes. In future we will combine live imaging HA with IAV ribonucleoproteins to get a high resolution complete look at IAV morphogenesis.

Studies on novel broad spectrum mechanisms of antiviral innate immunity:

Antiviral innate immune response in mammalian cells is centered around induction of Interferons and subsequent IFN mediated induction antiviral genes. We have identified novel mechanisms by which a large number of well known and potential antiviral genes are induced without the requirement of IFN signaling. Such IFN independent antiviral factors provide broad spectrum immunity against HIV, IAV, Herpes, Human parainfluenza, Dengue & Zika viruses. Mechanistic studies to characterize function of these antiviral factors are ongoing.