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Principal Investigator: Gaya K. Amarasinghe
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $3,374,001
Funding agency: National Institute of Allergy and Infectious Diseases
Overall Project Summary/Abstract: Molecular mechanisms of filoviral-host interactions
The family Filoviridae, which includes Ebola virus (EBOV) and Marburg virus (MARV), are zoonotic pathogens
that cause outbreaks of severe human disease and require biosafety level 4 (BSL4) containment for study.
Recent approval of a vaccine and antibody-based therapies against an EBOV represent progress towards
medical countermeasures. However, the family is comprised of multiple antigenically distinct species, making
identification of pan-filoviral therapeutic approaches desirable. Furthermore, the molecular mechanisms required
for replication and pathogenesis are incompletely understood. Defining key filovirus-host interactions and the
mechanisms by which they promote viral growth and disease will provide important insight into viral biology and
suggest new therapeutic approaches. Existing data, including our own, have identified key host-viral interactions
that likely play important roles in the pathogenesis of filovirus disease. Our overarching goal is to address this
gap in knowledge by building and expanding upon the strong foundational knowledge on EBOV to define
molecular mechanisms at the host-pathogen interface and to identify EBOV-specific and pan-filoviral interactions
that contribute to pathogenesis. To achieve our goals, we have assembled a highly accomplished team with
track records of effective synergistic collaboration and expertise ranging from molecular biochemistry, structural
biology and mass spectrometry to cell biology, virology, and work at BSL4. In the current funding period, we
identified multiple host pathways that impact EBOV infection and defined key interactions at the viral-host
interface. In our proposed studies, we use a reductionist approach to define molecular mechanisms by
biochemical and structural methods (Project 1; RP01), determine the cellular impact and contributions of viral
proteins such as VP30 and VP24 in immune response, viral replication, assembly and egress (Project 2; RP02),
and evaluate the impact of specific interactions with EBOV and MARV virus in cell culture and in vivo, including
specific subnetworks that regulate filoviral entry and replication (Project 3; RP03). Recognizing the complexity
of the data being generated we have recruited new expertise in proteomics and genetic network analysis to
provide a deeper understanding of host-virus protein connectivity and interaction. These efforts will be further
supported by two scientific cores, the Antibody and Reagent Development Core B and the BSL4/ABSL4
laboratory Core C. This work will be guided by an active Administrative Core A that will receive critical input from
the Core A Advisory Group (CAAG) and the External Advisory Board (EAB). Each is comprised of preeminent
scientists in academia and industry with strong productivity in emerging infectious diseases and immunology and
significant advisory experience. Building on our productive initial work, we are poised to define a comprehensive
host interaction network, validate regulatory mechanisms that drive viral infection, and identify targets for
therapeutic intervention. Our unique innovative experimental framework and highly interactive scientific
approach provides a blueprint to tackle other emerging and reemerging pathogens.
Terms: <Academia><Actins><Address><Antibodies><Antibody Therapy><Assay><Bioassay><Biochemical><Biochemistry><Biological><Biological Assay><Biological Chemistry><Biology><CRISPR><CRISPR/Cas system><Cell Body><Cell Culture Techniques><Cell Line><CellLine><Cells><Cellular biology><Clustered Regularly Interspaced Short Palindromic Repeats><Collaborations><Complex><Computer Assisted><Containment><Cryo-electron Microscopy><Cryoelectron Microscopy><Data><Development><Disease><Disease Outbreaks><Disorder><Distant><EBOV><Ebola virus><Ebola-like Viruses><Electron Cryomicroscopy><Emerging Communicable Diseases><Emerging Infectious Diseases><Ensure><Evaluation><Family><Family member><Filoviridae><Filoviridae Infections><Filovirus><Frankfurt-Marburg Syndrome Virus><Funding><Gene Transcription><Generalized Growth><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><Growth><HLA-DR Associated Protein II><Host Factor><Host Factor Protein><IGAAD><Immune response><Immunological response><Immunology><Industry><Infection><Inhibitor of GZMA-Activated DNase><Integration Host Factors><Investigators><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Laboratories><Learning><Maps><Marburg><Marburg Virus Disease><Marburg hemorrhagic fever><Marburg virus><Marburg-like Viruses><Marburgvirus><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Methods><Modeling><Molecular><Mutation><Network Analysis><Nucleocapsid><Null Mouse><Outbreaks><P01 Mechanism><P01 Program><Pathogenesis><Pathway Analysis><Pathway interactions><Periodicals><Phenotype><Phosphatase 2A Inhibitor I2PP2A><Physical condensation><Play><Predisposition><Productivity><Program Project Grant><Program Research Project Grants><Progress Reports><Protein Interaction Map><Protein-Protein Interaction Map><Proteins><Proteomics><Public Health><Publications><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Expression><RNA Processing><Reagent><Records><Research><Research Grants><Research Personnel><Research Program Projects><Research Project Grants><Research Projects><Research Resources><Researchers><Resource Sharing><Resources><Rodent><Rodentia><Rodents Mammals><Role><SET Translocation Inhibitor-2 of Protein Phosphatase-2A><Scientific Publication><Scientist><Set protein><Strains Cell Lines><Susceptibility><System><Template Activating Factor I Beta><Testing><Therapeutic><Therapeutic Intervention><Tissue Growth><Transcription><Transgenic Organisms><Vaccines><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virion><Virus><Virus Assembly><Virus Diseases><Virus Particle><Virus Replication><Virus-like particle><Work><Zoonoses><Zoonotic><Zoonotic Infection><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><biologic><cell biology><cell culture><cell cultures><cell type><computer aided><condensation><conditional knock-out><conditional knockout><cryo-EM><cryoEM><cryogenic electron microscopy><cultured cell line><data complexity><data sharing><developmental><emerging pathogen><experience><filovirus infections><genome mutation><host response><human disease><immune system response><immunoresponse><in vivo><innovate><innovation><innovative><insight><interdisciplinary approach><intervention therapy><medical countermeasure><mouse model><multidisciplinary approach><murine model><new drug target><new druggable target><new pathogen><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pathogen><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><ontogeny><pathogen><pathway><periodic><periodical><protein protein interaction><recruit><social role><structural biology><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tomography><training opportunity><transgenic><viral assembly><viral infection><viral multiplication><viral replication><virology><virus infection><virus multiplication><virus protein><virus-induced disease><virus-like nanoparticles><viruslike particle>