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Principal Investigator: Matthew Scott Kelly
Organization: DUKE UNIVERSITY
Fiscal Year: 2023
Award: $241,500
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
SARS-CoV-2, the etiological agent of COVID-19, has been responsible for more than 600 million reported
infections and 6.5 million deaths globally. Although several antivirals, monoclonal antibodies, and
immunomodulatory treatments improve patient outcomes, mortality from COVID-19 remains unacceptably high.
Moreover, despite mitigation measures and development of several highly effective vaccines, SARS-CoV-2 has
continued to spread globally, making it almost certain that the virus will become endemic in human populations.
There is therefore a critical need to identify host factors that modify SARS-CoV-2 susceptibility and severity to
guide infection prevention strategies and inform future vaccine and therapeutic development studies. SARS-
CoV-2 human challenge experiments provide an unprecedented opportunity to study these host factors by
standardizing the viral inoculum, the precise timing of viral exposure, and environmental conditions, thereby
controlling for factors that inevitably confound natural infection studies. The overall objective of this proposal is
to identify upper respiratory microbiome features and host gene expression profiles that modify susceptibility to
and symptoms of SARS-CoV-2 infection. This research will leverage previously collected clinical data and
samples from a first-in-human SARS-CoV-2 challenge study conducted in healthy adults without serological
evidence of prior infection or vaccination. We will perform shotgun metagenomic and RNA sequencing of serially
collected mid-turbinate nasal samples from 34 adults who were inoculated with a wild-type virus (SARS-CoV-
2/human/GBR/484861/2020), 18 (53%) of whom developed PCR-confirmed infection. In Aim 1, we will use nasal
samples collected at baseline and immediately following viral inoculation (days -1 to +3) to identify microbiome
features and host transcriptional responses associated with resistance to SARS-CoV-2 infection. In Aim 2, we
will use nasal samples collected between days -1 and +14 to characterize changes in the upper respiratory
microbiome and host transcriptome that occur during SARS-CoV-2 infection and correlate microbiome and
transcriptome profiles with the presence and severity of specific symptoms of SARS-CoV-2 infection. In both
Aims, we will use innovative multi-omics analyses to identify relationships between patient characteristics, upper
respiratory microbiome-transcriptome profiles, and SARS-CoV-2 susceptibility and symptoms. This research will
identify upper respiratory bacterial species associated with susceptibility to and symptoms of SARS-CoV-2
infection and could lead to development of rationally designed probiotics that prevent SARS-CoV-2 infection.
Further, a detailed understanding of the host responses that occur in the upper respiratory tract following SARS-
CoV-2 exposure and infection could inform development of nasal vaccines and identify novel targets for host-
directed diagnostics or therapeutics. Finally, analyses integrating microbiome and host transcriptome data will
elucidate mechanisms by which the upper respiratory microbiota and host immune system interact to influence
susceptibility to and severity of infections caused by SARS-CoV-2 and other respiratory viruses.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><21+ years old><ACE2><Adult><Adult Human><Age Years><Antibody Therapy><Antiviral Agents><Antiviral Drugs><Antivirals><Biological Response Modifier Therapy><Biological Therapy><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 exposure><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infection><COVID-19 mortality><COVID-19 predisposition><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 susceptibility><COVID-19 therapy><COVID-19 treatment><COVID-19 vaccination><COVID-19 vaccine><COVID-19 virus><COVID-19 virus infection><COVID-19 vulnerability><COVID19><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 therapy><COVID19 treatment><COVID19 vaccination><COVID19 vaccine><COVID19 virus><CV-19><CV19><Causality><Cessation of life><Characteristics><Clinical Data><Clinical Treatment Moab><CoV-2><CoV2><Conchae Nasales><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Corynebacterium><D pneumoniae><D. pneumoniae><Data><Death><Development><Diagnostic><Diplococcus pneumoniae><Education><Educational aspects><Epitheliasin Gene><Etiology><Foundations><Future><Gene Expression><Gene Transcription><Genes><Genetic Transcription><H influenzae><H. influenzae><Haemophilus influenzae><History><Host Defense><Host Factor><Host Factor Protein><Hour><Human><IFN><Immune><Immune Modulation Therapy><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Infection><Infection prevention><Inflammatory><Integration Host Factors><Interferons><Intranasal Administration><Intranasal Drug Administration><Measures><Microbe><Modeling><Modern Man><Monoclonal Antibodies><Nasal><Nasal Passages Nose><Nasal turbinate bone structure><Nose><Outcome><PRSS10><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Play><Pneumococcus><Population><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Predisposition><Prevent infection><Preventative strategy><Prevention strategy><Preventive strategy><Probiotics><Pulmonary Body System><Pulmonary Organ System><RNA Expression><RNA Helicase><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Recording of previous events><Reporting><Research><Resistance><Respiratory System><Respiratory System, Nose, Nasal Passages><Respiratory Tracts><Respiratory tract structure><Risk><Role><S pneumoniae><S. pneumoniae><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 exposure><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 predisposition><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 susceptibility><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV-2 vulnerability><SARS-CoV2><SARS-CoV2 exposure><SARS-CoV2 infection><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Serology><Severe Acute Respiratory Coronavirus 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microbes><beneficial microflora><beneficial microorganism><biological therapeutic><biological treatment><biologically based therapeutics><biotherapeutics><biotherapy><causation><commensal flora><commensal microbes><commensal microbiota><commensal microflora><corona virus disease 2019><corona virus disease 2019 vaccine><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 exposure><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 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disease 2019><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine development><vaccine for novel coronavirus><viral respiratory infection>