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Principal Investigator: Kartik Chandran
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $2,708,082
Funding agency: National Institute of Allergy and Infectious Diseases
Viruses interact with and hijack a vast array of cellular molecules and pathways to facilitate their multiplication
and spread, while also reprograming infected cells to release pathogenic viral factors (‘viral toxins’) that could
be independently targeted with vaccines and therapeutics to reduce disease severity. Given that virus-host
interactions can provide new and broadly shared Achilles’ heels against emerging viruses and inform the rapid
development of in vitro and in vivo models to test novel medical countermeasures, uncovering these interactions
is essential to pandemic preparedness. However, critical gaps exist in our foundational knowledge of the
mechanisms of viral infection and pathogenesis for nairoviruses, hantaviruses, and paramyxoviruses. The
overarching goal of Project 1 is to discover and dissect host factors and pathways critical for infection and
pathogenesis by our prototype viruses—Crimean-Congo hemorrhagic fever virus (CCHFV), Andes virus (ANDV),
and Menangle virus (MenPV)—and additional divergent viruses from these families. In Aim 1, our
interdisciplinary research team will discover and validate entry receptors and other critical host factors using
complementary CRISPR/Cas9-based genetic and time-resolved proteomic and phosphoproteomic screening
approaches, and selected hits will be assessed for their roles in infection and pathogenesis in vivo with gene-
edited rodent models of infection. Utilizing a suite of virological, cell-biological, and quantitative proteomics
assays, in Aim 2 we will elucidate the mechanisms by which our prototype viruses exploit validated host factors
and pathways, identify host interactors of viral proteins, and map the functional surfaces of viral and host proteins
confirmed to interact. These findings will be expanded to divergent members of each virus family. Finally, in Aim
3, our team will define the role of CCHFV and hantavirus glycoprotein-induced vascular leak in pathogenesis by
defining host factors and molecular interfaces essential for barrier dysfunction and identifying markers of
endothelial dysfunction in animal models and humans. Key deliverables of Project 1 include novel reagents,
including recombinant vesicular stomatitis viruses and variable heavy chain-only antibodies to facilitate host
factor discovery and validation, and critical data to support immunogen engineering efforts in Projects 2–3,
antibody profiling and discovery in Project 4, and animal model development in Core D. This project will
contribute to PROVIDENT's objectives by generating fundamental knowledge about virus-host interactions that
influence nairovirus, hantavirus, and paramyxovirus infection, virulence, and pathogenesis.
Terms: <2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><Alpaca><Andes Virus><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antigens><Antisera><Assay><Autoregulation><Bioassay><Biological><Biological Assay><Bleeding><Blood Serum><Blood Vessels><COVID-19 S protein><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cell surface><Cells><Clinical Treatment Moab><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Co-Immunoprecipitations><Collaborations><Congo Virus><Congo hemorrhagic fever virus><Crimean Hemorrhagic Fever Virus><Crimean-Congo Hemorrhagic Fever Virus><Crimean-Congo hemorrhagic fever orthonairovirus><Critical Paths><Critical Pathways><Culturing, in vitro Vertebrate, Primary><Data><Development><Dissection><Dysfunction><Endothelium><Engineering><Epithelium><Family><Flavivirus><Foundations><Functional disorder><Genes><Genetic><Genetic Processes><Genetic Screening><Genetics-Mutagenesis><Glycans><Glycoproteins><Goals><Golden Hamsters><Golden Syrian Hamsters><Group B Arbovirus><Hantavirus><Hantavirus Infections><Hemorrhage><Homeostasis><Host Factor><Host Factor Protein><Hu-mABs><Human><Immune Sera><Immunize><Immunotherapeutic agent><In Vitro><Infection><Integration Host Factors><Interdisciplinary Research><Interdisciplinary Study><Investigation><Knowledge><Life Cycle><Life Cycle Stages><Mammalian Cell><Maps><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Mesocricetus auratus><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Monoclonal Antibodies><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><Mutagenesis><Mutagenesis Molecular Biology><Nairovirus><Orthoflavivirus><Paramyxoviridae><Paramyxovirus><Pathogenesis><Pathogenicity><Pathologic><Pathology><Pathway interactions><Permeability><Phase><Physiological Homeostasis><Physiopathology><Polysaccharides><Position><Positioning Attribute><Primary Cell Cultures><Production><Proteins><Proteomics><R-Series Research Projects><R01 Mechanism><R01 Program><Reagent><Receptor Protein><Recombinants><Research Grants><Research Project Grants><Research Projects><Rodent Model><Role><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><Sampling><Serum><Services><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severity of illness><Surface><Syrian Hamsters><Testing><Therapeutic><Time><Toxin><Transgenic Animals><VSV><Vaccinated><Vaccines><Validation><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Pathogenesis><Viral Proteins><Virion><Virulence><Virus><Virus Diseases><Virus Particle><animal model development><biologic><biomarker identification><blood loss><candidate validation><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><design><designing><developmental><disease severity><emergent virus><emerging virus><endothelial dysfunction><evaluate vaccines><genetic approach><genetic strategy><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><identification of biomarkers><identification of new biomarkers><immune drugs><immune response to vaccination><immune response to vaccines><immune serum><immune-based therapeutics><immunogen><immunologic therapeutics><immunotherapeutics><immunotherapy agent><in vivo><in vivo Model><life course><mAbs><marker identification><medical countermeasure><member><model of animal><monoclonal Abs><novel><pandemic disease preparedness><pandemic planning><pandemic preparedness><pandemic readiness><pathophysiology><pathway><phospho-proteomics><phosphoproteomics><prevent><preventing><protein complex><prototype><receptor><screening><screenings><social role><spike proteins on SARS-CoV-2><vaccine associated immune response><vaccine evaluation><vaccine immune response><vaccine immunogenicity><vaccine induced immune response><vaccine screening><vaccine strategy><vaccine testing><validations><vascular><viral emergence><viral infection><viral infection mechanism><virology><virus host interaction><virus infection><virus infection mechanism><virus pathogenesis><virus protein><virus-induced disease>