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Principal Investigator: Ronald G Collman
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $243,750
Funding agency: National Institute of Dental and Craniofacial Research
The Oropharyngeal Microbiome in COVID-19
Summary (Abstract)
SARS-CoV-2 first infects the oropharynx and upper respiratory tract, where it either remains localized and is
cleared, or propagates to the lower respiratory tract where it can progress to pneumonia and respiratory failure.
Several patient factors correlate with increased COVID-19 severity, including older age, obesity and diabetes,
but the mechanisms linking these factors to COVID-19 pathogenesis are incompletely understood. What
determines the extent of SARS-CoV-2 upper respiratory tract (URT) replication and whether infection remains
localized or propagates to the lower respiratory tract (LRT) is therefore a critical knowledge gap.
Studies with other respiratory viruses (RSV, influenza) suggest that the local URT microbiome can regulate
immune responses and influence lung consequences of infection. In addition, the SARS-CoV-2 receptor ACE2
is an interferon-stimulated gene, suggesting that it could be modulated by local microbiota. Thus, the microbiome
could play a key role in local SARS-CoV-2 replication and consequences of infection through mechanisms
involving both immune modulation and viral receptor expression. Furthermore, we and others have shown that
the oropharyngeal microbiome is the principal source of lung microbiota, which are derived from the URT by
microaspiration, and so factors that affect the oropharyngeal microbiota likely also impact the lung microbiome
with similar effects.
We investigated hospitalized COVID-19 patients and found that the oropharyngeal (OP) microbiome differed
markedly from healthy subjects and also from hospitalized patients with other illnesses. The OP microbiome at
early sampling points correlated with maximum disease severity over the course of hospitalization. The OP
microbiome also correlated with systemic immune parameters in blood. These findings raise the possibility that
the microbiome in the oropharynx and upper respiratory region may influence severity of COVID-19. However,
there is limited knowledge on the OP microbiome in groups and comorbidities (diabetes, obesity, elderly)
associated with severe COVID-19 disease that might underlie this relationship.
Our hypothesis is that the oropharyngeal microbiome plays a key role in regulating consequences of SARS-
CoV-2 infection through modulation of ACE2 expression and/or immunity that determine whether infection is
locally contained in the URT or propagates to LRT involvement to cause severe disease. This mechanism may
act locally within the URT and also, by URT-LRT microbiome crosstalk, on the LRT. Our aims are to:
(1) Define the oropharyngeal microbiome of individuals at risk of mild vs severe COVID-19, relationship
to expression of ACE2 and relevant mucosal genes, and to microbiome communities seen in early
COVID-19 patients.
(2) Determine the effect of human-derived oropharyngeal microbiome communities, introduced in a
novel murine model, on ACE2 and immune genes in oropharyngeal and lower airway epithelial cells.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><ACE2><Address><Affect><Age><Aged 65 and Over><Airway failure><Animal Model><Animal Models and Related Studies><BMI><BMI percentile><BMI z-score><Bacteria><Blood><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Body Surface><Body mass index><COVID disease severity><COVID infected patient><COVID patient><COVID positive patient><COVID severity><COVID-19><COVID-19 disease severity><COVID-19 infected patient><COVID-19 infection><COVID-19 pathogenesis><COVID-19 patient><COVID-19 positive patient><COVID-19 related risk><COVID-19 risk><COVID-19 risk factor><COVID-19 severity><COVID-19 virus><COVID-19 virus infection><COVID19 disease severity><COVID19 infection><COVID19 pathogenesis><COVID19 patient><COVID19 positive patient><COVID19 severity><COVID19 virus><CV-19><Cell Body><Cells><Cellular Immune Function><Clinical><CoV-2><CoV2><Communities><Coronavirus Infectious Disease 2019><Data><Diabetes Mellitus><Diathesis><Disease><Disease susceptibility><Disorder><Economics><Elderly><Environment><Epithelial Cells><Exhibits><Future><Gender><Genes><Genetic><Goals><Grippe><Hand><Heterogeneity><Hospital Admission><Hospitalization><Human><Human Figure><Human body><IFN><Immune><Immune response><Immunes><Immunity><Immunological response><Immunomodulation><Individual><Infection><Inflammation><Influenza><Innate Immune Response><Innate Immunity><Interferons><Knowledge><Link><Lower respiratory tract structure><Lung><Lung Respiratory System><Lymphatic cell><Lymphocyte><Lymphocytic><Marrow Neutrophil><Mice><Mice Mammals><Modeling><Modern Man><Modification><Mononuclear><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Nasopharynx><Native Immunity><Natural Immunity><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Non-Specific Immunity><Nonspecific Immunity><Obesity><Oropharyngeal><Oropharynx><Oropharynxs><Outcome><Patients><Persons><Phase><Play><Pneumonia><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Quetelet index><Receptor Protein><Research Specimen><Resolution><Respiratory Epithelium><Respiratory Failure><Rhinopharynx><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 disease severity><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 severity><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><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-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 infection><Severe acute respiratory syndrome related corona virus 2><Severities><Severity of illness><Shapes><Source><Specimen><Structure of respiratory epithelium><Therapeutic Intervention><Upper respiratory tract><Viral><Viral Receptor><Virus Receptors><Work><Wuhan coronavirus><above age 65><adiposity><advanced age><advanced disease><advanced illness><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged ≥65><ages><airway epithelium><airway microbiome><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-microbial><antimicrobial><aspirate><co-morbid><co-morbidity><cohort><comorbidity><coronavirus disease 2019><coronavirus disease 2019 disease severity><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pathogenesis><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 risk><coronavirus disease 2019 risk factor><coronavirus disease 2019 severity><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease severity><coronavirus disease-19><coronavirus disease-19 pathogenesis><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><corpulence><diabetes><diabetic><disease severity><dysbacteriosis><dysbiosis><dysbiotic><economic><endotracheal><gene function><geriatric><hCoV19><hands><host response><human old age (65+)><immune function><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><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><innovate><innovation><innovative><insight><intervention therapy><liability to disease><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><lower respiratory tract><lung microbial community><lung microbiome><lung microbiota><lymph cell><microbial><microbial consortia><microbial flora><microbial imbalance><microbiome><microbiota><microflora><microorganism><model of animal><mortality><mouse model><multispecies consortia><murine model><nCoV2><nasopharnygeal><neutrophil><novel><old age><oral pharyngeal><over 65 years><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 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><prototype><pulmonary><pulmonary microbial community><pulmonary microbiome><pulmonary microbiota><receptor><receptor expression><resolutions><respiratory><respiratory infection virus><respiratory microbiome><respiratory tract epithelium><respiratory tract microbiome><respiratory virus><response><risk associated with COVID-19><risk factor associated with COVID-19><risk factor related to COVID-19><risk related to COVID-19><senior citizen><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 disease severity><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 severity><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social><upper airway tract><≥65 years>