Daisy Leung

Associate Professor of Medicine, Associate Professor of Biochemistry and Molecular Biophysics, Associate Professor of Pathology and Immunology

    • Source: Scopus
    19992021

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    The overarching goal of my research program is to define molecular mechanisms at the hostpathogen interface. Within this program, a major focus at present is to define regulatory mechanisms that non-segmented negative strand RNA viruses (NNSVs), which include human respiratory syncytial virus (RSV), use to evade host immunity and hijack the host components to facilitate viral pathogenesis. To achieve this goal, I use a multidisciplinary approach that includes biochemical, structural, biological, and virological methods, to dissect interactions, define structural determinants, and define regulatory mechanisms. Currently, there are two areas of concentration: Mechanisms of RSV-mediated host immune evasion. Among the virally encoded proteins, two non-structural (NS) proteins, NS1 and NS2, are important for RSV-mediated host immune evasion. Expression of these proteins individually and in combination results in decreased type I interferon (IFN) induction. However, sequence analysis shows that only the orthopneumoviruses (human RSV, bovine RSV, pneumonia virus of mice) encode for these NS proteins and that other NNSVs lack them, confirming the unique nature of these two proteins and highlighting a unique evolutionary path taken by RSV to achieve effective immune suppression. Therefore, establishing the specific roles for RSV NS proteins is critical for defining the host response to RSV infections. However, the mechanisms are not well-defined. We recently solved the first structures of human RSV NS1 and NS2 proteins that have eluded the field and identified structural elements critical for host interactions, and that may be important for modulating host responses. In ongoing studies, we are developing methods to use genome-wide assays, such as proteomics and genetic approaches, to identify new candidates that modulate host immunity. Regulatory mechanisms that RSV uses to hijack the actin cytoskeleton. The actin cytoskeleton controls key cellular processes, including cell morphology, motility, and intercellular communication. Consistent with the foundational nature of the actin cytoskeleton to cellular function, many viruses have been reported to hijack the actin cytoskeleton. Elegant mechanistic understanding of the use of actin in vaccinia virus spread and baculovirus motility has emerged, highlighting the complex interplay between viral proteins and cytoskeletal factors that can underlie virus-induced utilization of the cytoskeleton. The actin cytoskeleton has been shown to play a key role in regulation of several steps in many other viral life cycles, including pneumoviruses like RSV; however, the molecular interactions involved have yet to be clearly deciphered. Current studies, including those from my group, have shown that components from RSV interact with the host actin cytoskeleton and that these interactions may facilitate infection, replication, egress, and to circumvent host defense mechanisms. Despite the critical impact RSV poses on human health, particularly in the pediatric, elderly, and immunocompromised populations, important processes in the viral life cycle remain poorly understood. Research directed toward exploring these important host-pathogen interactions will provide critical basic knowledge and insights into new interfaces that can be targeted for small molecule and antibody-based therapeutic development. I also expect to use this framework to evaluate other NNSVs with similar impact on human health, such as human metapneumovirus (HMPV), Ebola virus, and Marburg virus.

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