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Principal Investigator: Adolfo Garcia-Sastre
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $2,534,738
Funding agency: National Institute of Allergy and Infectious Diseases
Previous to the COVID-19 pandemic, we assembled, under the same U19 mechanism, a multidisciplinary
team to obtain multiple OMICS-based systems level measurements and integrate them using modeling
approaches and machine learning algorithms to identify and validate host-virus networks that modulate
influenza A virus disease severity, biomarkers in blood that reflect the activation states of these networks and
novel host targets for therapeutic interventions. As a result, we have identified important host factors and
pathways involved in antiviral response and virus replication and disease, leading to potential treatments. The
sudden onset of the COVID-19 pandemic in 2020 prompted us to redirect our systems biology efforts to study
SARS-CoV-2 infections. We now propose to continue these studies under this U19 renewal application entitled
SARS-CoV adaptations through a Systems Biology Lens (SYBIL). Our underlying main hypothesis is that
host networks involved in SARS-CoV replication and early host responses regulate disease outcomes and
represent targets for therapeutic intervention. As these viruses have a zoonotic origin in bats, we will also
explore virus-host networks involved in human adaptation and responsible for changing the tropism from the
original bat host to humans. In order to identify clinically relevant networks involved in SARS-CoV replication,
pathogenesis and host tropism we propose to integrate into predictive and comprehensive models global
responses during infection in three systems 1) human blood and respiratory samples from human cohorts with
documented SARS-CoV infection and diverse clinical outcomes (Project 1); 2) blood and tissues from
experimentally infected animals under a variety of conditions and perturbations resulting in diverse disease
outcomes (Project 1) and 3) human and bat cells subjected to viral protein expression, genetic screens and
infection with diverse SARS-CoVs, including primary cells derived from iPSC precursors (Project 2). Samples
will be processed and send to the Technology Core for global transcriptomics, epigenetics, proteomics and
functional genomics analysis. OMICS data sets will be integrated and compared by the Modeling Core to
generate specific hypothesis and network models of disease, uncover blood biomarkers and identify host and
virus key drivers of viral replication, host response, disease outcome and host tropism. Predicted network
regulators will be used as a source for subsequent iterative rounds of perturbations to refine existing and to
identify new network models. Data and models will be managed and disseminated by the Data Management
and Bioinformatics Core. We expect that these studies will uncover novel virus-host pathogenic networks,
blood biomarkers associated with them, determinants of human adaptation and specific therapeutic targets. In
summary, our modeling approaches will find associations between diverse experimental systems that will help
us define determinants associated with SARS-CoV bat-human host jumping COVID-19 severity, and link them
to in vivo and ex vivo signatures for risk assessment, companion diagnostics and personalized therapies.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Animal Model><Animal Models and Related Studies><Animals><Anti-viral Response><Appearance><Bats><Bio-Informatics><Bioinformatics><Biological><Biological Markers><Blood><Blood Reticuloendothelial System><Body Tissues><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 infection><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 severity><COVID-19 virus><COVID-19 virus infection><COVID-19 years><COVID19 disease severity><COVID19 infection><COVID19 severity><COVID19 virus><CV-19><Cell Body><Cells><Cessation of life><Chiroptera><Clinical><Clinical Trials><CoV-2><CoV2><Communities><Coronaviridae Infections><Coronavirus Infections><Coronavirus Infectious Disease 2019><Data><Data Set><Death><Diabetes Mellitus><Disease><Disease Outcome><Disease Progression><Disorder><Drugs><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Experimental Models><Generations><Genes><Genetic Screening><Grippe><Host Factor><Host Factor Protein><Human><Illumination><Immune response><Immunological response><Infection><Influenza><Influenza A><Influenza A virus><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Integration Host Factors><Intervention><Intervention Strategies><Lighting><Link><Measurement><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Murine><Mus><Obesity><Orthomyxovirus Type A><Outcome><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Pharmaceutical Preparations><Process><Progress Reports><Proteome><Proteomics><Research><Risk Assessment><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 infection><SARS-CoV-2 pandemic><SARS-CoV-2 severity><SARS-CoV2><SARS-CoV2 infection><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><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 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Source><Specific qualifier value><Specified><System><Systems Biology><Technology><Testing><Therapeutic Intervention><Tissues><Tropism><Type A Influenza><Vaccination><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><adiposity><bio-markers><biologic><biologic marker><biomarker><biomarker identification><clinical relevance><clinically relevant><cohort><companion diagnostics><computer based prediction><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 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 severity><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><corpulence><cross-species spillover><cross-species transmission><data integration><data management><diabetes><disease model><disease severity><disorder model><drug/agent><epigenetically><epigenome><flu infection><flu virus infection><functional genomics><global gene expression><global transcription profile><hCoV19><host jump><host response><host switching><iPS><iPSC><iPSCs><identification of biomarkers><identification of new biomarkers><immune system response><immunological status><immunoresponse><improved><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><infected with severe acute respiratory syndrome coronavirus 2><influenza infection><influenza virus infection><influenzavirus><insight><interspecies transmission><intervention therapy><interventional strategy><lens><lenses><machine learned algorithm><machine learning algorithm><machine learning based algorithm><marker identification><metabolome><metabonome><model of animal><molecular profile><molecular signature><mouse model><multidisciplinary><multiomics><multiple omics><murine model><mutant><nCoV2><network models><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><novel virus><pandemic><pandemic disease><panomics><pathogen><pathway><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><predictive biomarkers><predictive marker><predictive modeling><predictive molecular biomarker><programs><protein expression><respiratory><response><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-CoV><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><transcriptome><transcriptomics><transmission across species><transmission between species><transmitted across species><transmitted between species><transmitted cross-species><validations><viral infection><viral multiplication><viral replication><virus host interaction><virus infection><virus multiplication><virus protein><virus-induced disease>