Mechanisms of Actin Cytoskeleton Modulation by Pneumoviruses

Grants and Contracts Details

Description

The actin cytoskeleton controls key cellular processes, including cell morphology, motility, and intercellular communication. Many viral pathogens exploit the actin cytoskeletal machinery by a variety of unique mechanisms to facilitate viral infection, replication, and egress. Currently, the molecular underpinnings of these viral mechanisms remain poorly defined for a majority of viruses, including members of the Pneumoviridae family. Human respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are non-segmented negative strand RNA viruses (NNSVs) that encode for 11 and 9 functional proteins, respectively, and are members of the recently created Pneumoviridae family. RSV and HMPV cause significant disease, including bronchiolitis and lower respiratory tract infection in the pediatric population, elderly, and immunocompromised individuals. Recent studies from our groups and others have implicated interactions between actin or actin-interacting proteins and specific pneumovirus proteins in replication and viral spread; however, the mechanisms and cellular targets required for facilitating actin rearrangements and shuttling viral replication centers remain unknown. Our overall hypothesis is that a cascade of specific interactions between pneumovirus proteins and the actin cytoskeleton regulate key steps in viral infection, including formation of novel structures critical for virus spread. Our collaborative team, with expertise in virology, cell biology, biochemistry, and structural biology, will test our hypothesis through three specific aims. First, we will define the molecular mechanism(s) by which the RSV and HMPV matrix (M) proteins and phosphoproteins (P) regulate the actin cytoskeleton within an infected cell. Second, we will determine the biochemical and structural basis for HMPV phosphoprotein/matrix/actin complex and hRSV P/M/actin complex. Finally, we will determine the mechanisms of intercellular extension formation, stabilization, and utilization in viral spread. At the completion of these studies, we expect to define molecular mechanisms by which RSV and HMPV interact with and modulate the host actin cytoskeleton during virus replication and identify key regulatory viral proteins. Our studies will also provide a critical framework to delineate a role for actin-viral interactions in pathogenesis of negative strand virus infection by hijacking components from the actin cytoskeletal network. Collectively, we expect to delineate key processes that facilitate virus replication and spread and define previously unrecognized therapeutic targets.
StatusActive
Effective start/end date6/11/185/31/24

Funding

  • National Institute of Allergy and Infectious Diseases: $3,278,717.00

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