Document text
Principal Investigator: ALAN R HAUSER
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2021
Award: $749,891
Funding agency: National Institute of Allergy and Infectious Diseases
SARS-CoV-2, the cause of the COVID-19 pandemic, emerged from Wuhan, China, and rapidly spread
around the world. A feature of the pandemic has been the repeated emergence of SARS-CoV-2 clades and
variants of concern, some of which have been shown to have enhanced transmissibility. Other aspects of
these lineages, however, remain unclear. The vast majority of the 3.75 million deaths caused by SARS-CoV-2
are the result of severe pneumonia. In these patients, ongoing SARS-CoV-2 viral replication in the lungs leads
to slowly progressing pulmonary injury and subsequent respiratory failure. Yet our understanding of the genetic
evolution of SARS-CoV-2 in the lungs is limited because of difficulties sampling the pulmonary alveolar space
and in linking viral samples to robust and comprehensive clinical data. In this regard, the Successful Clinical
Response in Pneumonia Therapy (SCRIPT) Systems Biology Center provides the ideal infrastructure to collect
deep-lung viral samples and corresponding immune response and clinical metadata from patients with COVID-
19. We propose to leverage the clinical and research infrastructure of SCRIPT to study SARS-CoV-2 variants
and intra-host adaptation. We will expand SCRIPT to link patient phenotypes with virus genotypes. Our
hypothesis is that SARS-CoV-2 clades influence the severity of COVID-19 pneumonia and that viral
diversity evolves in the lungs of patients experiencing severe pneumonia. To test our hypotheses, we will
perform the following specific aims: Aim 1. We will determine whether specific SARS-CoV-2 clades are
associated with greater disease severity or altered host response. We will sequence SARS-CoV-2
isolates from a biobank of a general pool of COVID-19 patients at our institution and from BAL samples of
intubated patients with severe COVID-19 pneumonia to establish their genotypes. Associations between
specific SARS-CoV-2 clades and disease severity and outcomes in both populations will be sought. Aim 2. We
will examine the evolution of intra-host SARS-CoV-2 viral sequence changes over time in the lungs of
patients with severe COVID-19 pneumonia. In a subset of patients with prolonged respiratory failure, we will
sequence viral isolates and examine the host immune response using longitudinally collected serial BAL
samples. These data will be used to quantify viral dynamics in the lung, to map the intra-host emergence of
viral quasi-species, to characterize the host immune responses elicited by these changes, and to correlate
these features with the clinical conditions of the patients. Aim 3. We will generate a computational model
that integrates SARS-CoV-2 clade genome information with clinical and host immune response
features to predict the severity of COVID-19 infections. Viral clade data will be integrated with measures of
the host immune response (BAL fluid flow cytometry and cytokine levels) and patient clinical metadata to
develop a comprehensive model that predicts which patients will develop especially severe COVID-19 disease.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><A baumanni><A baumannii><A. baumanni><A. baumannii><A.baumannii><Acinetobacter baumanni><Acinetobacter baumannii><Alveolar><Archives><Bacterial Pneumonia><Breathing><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchoalveolar Lavage Fluid><Bronchopulmonary Lavage><COVID associated pneumonia><COVID crisis><COVID disease severity><COVID epidemic><COVID induced pneumonia><COVID infected patient><COVID pandemic><COVID patient><COVID pneumonia><COVID positive patient><COVID related pneumonia><COVID severity><COVID-19><COVID-19 associated pneumonia><COVID-19 crisis><COVID-19 disease severity><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced pneumonia><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 pneumonia><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related pneumonia><COVID-19 severity><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID19><COVID19 crisis><COVID19 disease severity><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 severity><COVID19 virus><CV-19><CV19><Calymmatobacterium><Cause of Death><China><Clinical><Clinical Data><CoV-2><CoV2><Computer Models><Computerized Models><Data><Development><Disease><Disease Outcome><Disease Progression><Disorder><Donovania><Evolution><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Funding><Genetic Alteration><Genetic Change><Genetic defect><Genome><Genotype><Goals><Host Factor><Host Factor Protein><Immune><Immune response><Immunes><Immunological response><Infection><Inflammation><Infrastructure><Injury><Institution><Integration Host Factors><Klebsiella><Knowledge><Link><Lung><Lung Lavage><Lung Respiratory System><Mainland China><Maps><Measurement><Measures><Mechanical ventilation><Metadata><Morbidity><Morbidity - disease rate><Mutate><Mutation><NIAID><National Institute of Allergy and Infectious Disease><Non-Polyadenylated RNA><Outcome><P aeruginosa><P. aeruginosa><Patients><Phenotype><Pneumonia><Population><Process><Pseudomonas aeruginosa><Pseudomonas pyocyanea><RNA><RNA Gene Products><Research Infrastructure><Respiratory Aspiration><Respiratory Failure><Respiratory Inspiration><Ribonucleic Acid><Risk><S aureus><S. aureus><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 associated pneumonia><SARS-CoV-2 disease severity><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced pneumonia><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 pneumonia><SARS-CoV-2 positive patient><SARS-CoV-2 related pneumonia><SARS-CoV-2 severity><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><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 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-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome 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><Staph aureus><Staphylococcus aureus><Systems Biology><Testing><Time><Viral><Virus><Virus Replication><Work><Writing><Wuhan coronavirus><bacteria pneumonia><bacterial microbiome><bacteriome><biobank><biorepository><bronchopulmonary lavage therapy><clinical infrastructure><cohort><computational modeling><computational models><computer based models><computer based prediction><computerized modeling><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 associated pneumonia><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 induced pneumonia><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 pneumonia><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 related pneumonia><coronavirus disease 2019 severity><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease associated pneumonia><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease induced pneumonia><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease pneumonia><coronavirus disease positive patient><coronavirus disease related pneumonia><coronavirus disease severity><coronavirus patient><cytokine><developmental><disease severity><experience><flow cytophotometry><genetic evolution><genome mutation><hCoV19><host response><immune system response><immunoresponse><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><injuries><insight><inspiration><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lung failure><mechanical respiratory assist><mechanically ventilated><meta data><microbiome><mortality><nCoV2><pandemic><pandemic disease><pathogen><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient subgroups><patient subpopulations><patient subsets><patient subtypes><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><pneumonia due to COVID><pneumonia due to COVID-19><pneumonia due to SARS-CoV-2><pneumonia due to coronavirus disease><pneumonia due to coronavirus disease 2019><pneumonia due to severe acute respiratory syndrome coronavirus 2><pneumonia in COVID><pneumonia in COVID-19><pneumonia in SARS-CoV-2><pneumonia in coronavirus disease><pneumonia in coronavirus disease 2019><pneumonia in severe acute respiratory syndrome coronavirus 2><pneumonia therapy><pneumonia treatment><prediction model><predictive modeling><pulmonary><pulmonary failure><response><scRNA-seq><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 associated pneumonia><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 induced pneumonia><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 pneumonia><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related pneumonia><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 coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><single cell RNA-seq><single cell RNAseq><single-cell RNA sequencing><treat pneumonia><variants of concern><viral multiplication><viral replication><virus envelope><virus multiplication>