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Principal Investigator: Adolfo Garcia-Sastre
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $702,405
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT 2: Ex Vivo Analysis of Coronavirus Tropism, Adaptation, Replication, and Host Response
In this proposal, we hypothesize that multiple and discrete virus-host interactions and host responses to
infection dictate the pathogenic outcome and host tropism of SARS-CoV-2. We further hypothesize that these
critical circuits can be dissected through network-based modeling of system-level measurements offering the
potential for the development of novel antiviral therapies. In Project 2, we propose to utilize leading edge OMICs-
based measurements to define virus-host interactions and networks that control viral replication, viral
tropism/adaptation and host responses across bat coronaviruses, SARS-CoV-1, and SARS-CoV-2 variants. In
Aim 1, we will conduct proteomics (AP-MS, protein abundance and post-translational modifications),
transcriptomics (RNA-seq and scRNA-seq), epigenomics (ATAC-seq, Hi-C and ChiP-seq) and genetic and
chemical compound screens using ex vivo primary epithelial cells and iPSC-derived pneumocytes derived both
from human and bats and a lung epithelial cell line (A549). In Aim 2, these data will be integrated and modeled
with in vivo and clinical data collected in Project 1 using network-based predictive modeling approaches to
identify host proteins, networks, and pathways that correlate with disease severity and host adaptation (‘driver
genes’). Reiterative modeling of data generated in Aim 1 and Project 1 will be employed to refine these
predictions. In Aim 3, CRISPR-editing approaches will be used in concert with targeted OMICs measurements
(CRISPR-OMICs), including transcriptional, epigenetic, proteomic analyses, to validate the impact of these
‘driver genes’ on disease outcome and host tropism. Additional molecular, cellular, biochemical, and in vivo
studies will be conducted to further characterize nodes that determine disease outcome as potential therapeutic
targets. Overall, these studies will enable us to correlate in vivo and clinical biomarkers predictive of COVID-19
severity (Project 1) to specific genes and networks that impact viral infection, cellular host responses, and
interspecies transmission.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><A549><ATAC sequencing><ATAC-seq><ATACseq><Affect><Anti-viral Therapy><Appearance><Assay for Transposase-Accessible Chromatin using sequencing><Bats><Biochemical><Biologic Models><Biological><Biological Models><COVID crisis><COVID disease severity><COVID epidemic><COVID pandemic><COVID severity><COVID-19><COVID-19 crisis><COVID-19 disease severity><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 severity><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 years><COVID19 disease severity><COVID19 severity><COVID19 virus><CRISPR><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 system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CV-19><Candidate Disease Gene><Candidate Gene><Cas nuclease technology><Cell Body><Cell Line><CellLine><Cells><Cessation of life><ChIP Sequencing><ChIP-seq><ChIPseq><Chemicals><Chiroptera><Clinical><Clinical Data><Clinical Research><Clinical Study><Clustered Regularly Interspaced Short Palindromic Repeats><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><CoV-2><CoV2><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Data><Death><Development><Disease><Disease Outcome><Disease Progression><Disorder><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Gene Transcription><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Hi-C><Human><Immune><Immune response><Immunes><Immunological response><In vivo analysis><Infection><Inflammatory><Life Cycle><Life Cycle Stages><Link><Lung><Lung Respiratory System><Maps><Measurement><Mediating><Mice><Mice Mammals><Model System><Modeling><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Murine><Mus><Mutation><Network-based><Outcome><Pathogenicity><Pathway interactions><Peptide Domain><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Production><Protein Domains><Protein Modification><Proteins><Proteomics><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 disease severity><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 severity><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Sarbecovirus><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Strains Cell Lines><Systems Biology><Tertiary Protein Structure><Testing><Transcription><Transmission><Tropism><Validation><Variant><Variation><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus Diseases><Virus Replication><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biologic><candidate biomarker><candidate marker><cell type><chromatin immunoprecipitation-sequencing><clinical biomarkers><clinically useful biomarkers><computer based prediction><corona virus><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 disease severity><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 severity><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease severity><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus infectious disease-19><cross-species spillover><cross-species transmission><cultured cell line><cytokine><data integration><data modeling><design><designing><developmental><disease severity><epigenetically><epigenomics><experiment><experimental research><experimental study><experiments><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><genome mutation><hCoV19><host jump><host response><host switching><iPS><iPSC><iPSCs><immune system response><immunoresponse><improved><in silico><in vivo><in vivo Model><in vivo evaluation><in vivo testing><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><insight><interspecies transmission><knockout gene><lens><lenses><life course><loss of function><machine learned algorithm><machine learning algorithm><machine learning based algorithm><model of data><model the data><modeling of the data><molecular profile><molecular signature><mutant><nCoV2><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pandemic><pandemic disease><pathogen><pathway><pneumocyte><post SARS-CoV-2 infection><predictive biomarkers><predictive marker><predictive modeling><predictive molecular biomarker><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><protein expression><proteomic signature><pulmonary><receptor><response><scRNA-seq><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 severity><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><severe acute respiratory syndrome-CoV><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small molecule><social role><therapeutic target><transcriptome sequencing><transcriptomic sequencing><transcriptomics><transmission across species><transmission between species><transmission process><transmitted across species><transmitted between species><transmitted cross-species><validations><viral infection><viral infectious disease treatment><viral multiplication><viral replication><virus host interaction><virus infection><virus multiplication><virus protein><virus-induced disease>