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Principal Investigator: Katherine Camille Barnett
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $104,722
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Acute respiratory distress syndrome (ARDS) causes COVID-19 fatalities and is linked to uncontrolled
release of pro-inflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF).
Blockade of IL-1/IL-6 receptor signaling has shown success in treating severe COVID-19, but the molecular cues
initiating excessive production of these cytokines remains unclear. A major source of IL-1 is the inflammasome,
a supramolecular protein complex formed in response to two innate immune stimuli that executes IL-1β release.
Meta-analysis of patient single-cell RNA sequencing data reveals exacerbated expression of IL1B and
inflammasome-related genes in severe, but not mild, COVID-19. Co-culture of primary human airway epithelia
(HAE) and primary human leukocytes during SARS-CoV-2 infection promotes IL-1β release, while infection in
either cell type alone does not. These conditions also promote IL-6 release in an IL-1-dependent manner,
highlighting how inflammasome activation and cell-cell communication amplify this inflammatory response.
Furthermore, infected HAE undergo lytic cell death and secrete inflammasome-activating damage-associated
molecular patterns (DAMPs). Therefore, the scientific goal of this proposal is to understand how SARS-CoV-2
infection promotes pathologic inflammasome responses with the central hypothesis that damage from dying,
infected airway epithelial cells potentiate detrimental IL-1β release. Aim 1 will determine which inflammasome(s)
mediate harmful IL-1β responses during SARS-CoV-2 infection in vivo and identify the tissue(s) from which this
response is derived. Aim 2 will define the mechanism of SARS-CoV-2-mediated cell death in airway epithelial
cells and its relationship with inflammasome-mediated cell death in myeloid cells using an established primary
human co-culture system. Aim 3 will identify DAMPs released by infected primary human airway epithelial cells
that stimulate inflammasome response via an unbiased multi-omics approach. These studies will define how
damage caused by viral infection propagates inflammation and its role in disease, opening avenues for
therapeutic targeting and identifying biomarkers related to pathologic inflammation in COVID-19.
My goal is to become a tenured faculty member at a major research university with a research program
studying fatal and emerging viral pathogens. My group will focus its efforts on understanding the innate immune
response to viruses that regularly threaten human health and pinpoint pattern recognition receptor (PRR) ligands
that lead to detrimental patient outcomes. Using a combined approach of primary human cell culture models,
organismal murine models, and mechanistic molecular biology, I will identify readily translatable molecular
targets to treat human viral diseases. Herein, I outline both a scientific vision and a plan acquire new skills
through collaboration with local faculty, the support of my community and my advisory committee, and formal
coursework to enhance my abilities further, creating a framework for my success as an independent investigator.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><ARDS><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adaptor Protein><Adaptor Protein Gene><Adaptor Signaling Protein><Adaptor Signaling Protein Gene><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Advisory Committees><Apoptosis-Related Cysteine Protease Caspase 1><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Beta Proprotein Interleukin 1><Bleeding><Blood leukocyte><Body Tissues><Body Weight><Bystander Effect><CASP-1><CASP1><CASP1 gene><CD126 Antigens><CD126 Receptor><COVID infected patient><COVID patient><COVID positive patient><COVID test><COVID tests><COVID-19><COVID-19 antibody><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 infection><COVID-19 mortality><COVID-19 patient><COVID-19 positive patient><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 test><COVID-19 tests><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><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 patient><COVID19 positive patient><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 test><COVID19 tests><COVID19 virus><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 technology><CRISPR/Cas9><CRISPR/Cas9 technology><CV-19><Cachectin><Cas nuclease technology><Caspase-1><Caspase-1 Gene><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Culture Techniques><Cell Death><Cell Death Induction><Cell Interaction><Cell Signaling><Cell secretion><Cell-to-Cell Interaction><Cells><Cellular Secretion><Clinical Trials><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><Co-culture><CoV-2><CoV2><Cocultivation><Coculture><Coculture Techniques><Collaborations><Communities><Coronavirus Infectious Disease 2019><Cues><DNA><DNA Molecular Biology><Da Nang Lung><Data><Deoxyribonucleic Acid><Disease><Disorder><Envelope Protein><Epithelial Cells><Epithelium><Exogenous Factors><Faculty><Gene Deletion><Genes><Goals><HPGF><Health><Hemorrhage><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><ICE Protease><IFN-beta 2><IFNB2><IL-1><IL-1 beta><IL-1 beta Convertase><IL-1 beta-Converting Enzyme><IL-1 β><IL-1-b><IL-1BC><IL-1b Converting Enzyme><IL-1ra><IL-1β><IL-6><IL-6 Receptors><IL1><IL1 febrile inhibitor><IL1-Beta><IL1-β><IL1B Protein><IL1B-Convertase><IL1BC><IL1BCE><IL1F2><IL1RN><IL1β><IL6 Protein><IL6 Receptors><Immune><Immunes><In Vitro><In vivo analysis><Infection><Infection Control><Inflammasome><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Response><Innate Immune Response><Interleukin 1-B Converting Enzyme><Interleukin 1-Beta Convertase><Interleukin 1beta><Interleukin 6 Receptor><Interleukin I><Interleukin-1><Interleukin-1 Beta Converting Enzyme><Interleukin-1 Converting Enzyme><Interleukin-1 Receptor Antagonist><Interleukin-1 beta><Interleukin-1β><Interleukin-6><Intracellular Communication and Signaling><Investigators><Kinases><Leukocytes><Leukocytes Reticuloendothelial System><Ligands><Link><Lung><Lung Respiratory System><Lung damage><Lymphocyte-Stimulating Hormone><Lytic><MGI-2><Macrophage Cell Factor><Macrophage-Derived TNF><Marrow leukocyte><Mediating><Meta-Analysis><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Biology><Molecular Target><Monocyte-Derived TNF><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Myeloid Differentiation-Inducing Protein><Names><Outcome><Pathologic><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pattern><Pattern recognition receptor><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Plasmacytoma Growth Factor><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Preinterleukin 1 Beta><Production><Protein Modification><Protein Phosphorylation><Proteins><Receptor Protein><Receptor Signaling><Regulation><Research><Research Personnel><Researchers><Respiratory Epithelium><Role><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 antibody><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 test><SARS-CoV-2 tests><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><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><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><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><Shock Lung><Sight><Signal Transduction><Signal Transduction Systems><Signaling><Source><Stiff lung><Stimulus><Structure of respiratory epithelium><System><T Helper Factor><TLR protein><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Task Forces><Testing><Therapeutic><Tissues><Toll-Like Receptor Family Gene><Toll-like receptors><Transphosphorylases><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Universities><Viral Diseases><Virion><Virus><Virus Diseases><Virus Particle><Vision><White Blood Cells><White Cell><Work><Wuhan coronavirus><adapter protein><advisory team><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><airway epithelium><anakinra><antibody against COVID-19><antibody against SARS-CoV-2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody to COVID-19><antibody to SARS-CoV-2><antibody to coronavirus disease 2019><antibody to severe acute respiratory syndrome coronavirus 2><biological signal transduction><biomarker identification><blood loss><cell culture><cell cultures><cell type><coronavirus disease 2019><coronavirus disease 2019 antibody><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 test><coronavirus disease 2019 tests><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease test><coronavirus disease tests><coronavirus disease-19><coronavirus disease-19 mortality><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><coronavirus test><coronavirus tests><cytokine><cytokine release syndrome><cytokine storm><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><design><designing><env Antigens><env Gene Products><env Polyproteins><env Protein><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><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><gene deletion mutation><hCoV19><identification of biomarkers><identification of new biomarkers><in vivo><in vivo evaluation><in vivo testing><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><inflammatory mediator><insight><interferon beta 2><interleukin 1 receptor antagonist protein><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 injury><lymphocyte activating factor><marker identification><member><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><mouse model><multiomics><multiple omics><murine model><nCoV2><name><named><naming><necrocytosis><panomics><pathogen><pathogenic virus><pathway><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 oriented outcomes><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><post SARS-CoV-2 infection><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><programs><protein complex><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><receptor><respiratory tract epithelium><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 antibody><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome coronavirus 2 test><severe acute respiratory syndrome coronavirus 2 tests><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 expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skills><social role><success><test for COVID><therapeutic target><urine IL-1 inhibitor><urine interleukin 1 inhibitor><urine-derived IL1 inhibitor><viral infection><viral pathogen><virus infection><virus pathogen><virus-induced disease><visual function><wet lung><white blood cell><white blood corpuscle>