Targeting abnormal alveolar immune activation and failed epithelial repair in COVID-19

NIH Pandemic-Era Grants

Pandemic Era Grants

2022

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Principal Investigator: GR Scott  Budinger
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2022
Award: $742,194
Funding agency: National Heart Lung and Blood Institute

PROJECT SUMMARY
This application directly stems from our recent publication in Nature in which we analyzed bronchoalveolar
lavage (BAL) fluid from 88 patients with critical SARS-CoV-2 pneumonia using a combination of flow cytometry,
bulk transcriptomic profiling of flow sorted alveolar macrophages and, in some patients, single cell RNA-
sequencing. We compared these data with analogous samples collected from 211 patients with pneumonia
secondary to other pathogens before and during the pandemic with a goal of identifying unique pathobiologic
features of SARS-CoV-2 pneumonia. Using these data, we generated the hypothesis that SARS-CoV-2 causes
a slowly unfolding, spatially limited alveolitis in which alveolar macrophages harboring SARS-CoV-2 and
cross-reactive T cells form a positive feedback loop that drives progressive alveolar inflammation. We
address key questions from this hypothesis in three interrelated Specific Aims.
Aim 1. To determine whether alveolar macrophage infection and activation of cross-reactive memory T
cells drive alveolar macrophage/T cells circuits in patients with SARS-CoV-2 pneumonia. We will examine
the role of cross-reactive antibodies in mediating alveolar macrophage infection with SARS-CoV-2. We will also
examine the role of cross-reactive memory T cells recognizing SARS-CoV-2 and other coronaviruses in
establishing and maintaining positive feedback loops between T cells and infected alveolar macrophages and
the role of these signaling loops in initiating persistent lung and systemic inflammation.
Aim 2. To determine whether calcium channel activation by the envelope protein of SARS-CoV-2 is
necessary for activation of IL-1β in human alveolar macrophages. We will infect human alveolar
macrophages with mutant SARS-CoV-2 viruses lacking calcium channel activity in the envelope protein and
measure their generation of IL-1β in human alveolar macrophage in vitro.
Aim 3. To determine whether a pharmacologic inhibitor of CRAC channel activation can attenuate
alveolitis in patients with severe SARS-CoV-2 pneumonia by disrupting circuits between infected
alveolar macrophages and cross-reactive T cells. We are actively enrolling in a clinical trial to determine the
biologic effects of a small molecule inhibitor of CRAC channel activation using sequential analysis of BAL fluid
collected from patients with SARS-CoV-2 pneumonia requiring mechanical ventilation. We will use novel data
science approaches to integrate the clinical and genomic data generated from this study.
We have assembled a unique group of investigators with expertise in lung immunology, clinical trials, calcium
channels and virology. Our studies will explore possible reasons for the observed variability in disease severity
after SARS-CoV-2 infection, offer mechanisms to credential CRAC channel inhibitors as both anti-inflammatory
and possible antiviral therapeutics in patients with severe SARS-CoV-2 pneumonia, and provide a framework
for future clinical trials designed using biomarkers derived from bronchoalveolar lavage fluid.

Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><ARDS><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Alveolar><Alveolar Macrophages><Alveolitis><Animal Model><Animal Models and Related Studies><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Antigen-Presenting Cells><Antiinflammatories><Antiinflammatory Agents><Antiviral Agents><Antiviral Drugs><Antivirals><Attenuated><Beta Proprotein Interleukin 1><Biological><Biological Markers><Body Tissues><Bronchoalveolar Lavage Fluid><COVID associated pneumonia><COVID induced pneumonia><COVID infected patient><COVID patient><COVID pneumonia><COVID positive patient><COVID related pneumonia><COVID-19><COVID-19 associated pneumonia><COVID-19 induced pneumonia><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 pneumonia><COVID-19 positive patient><COVID-19 related pneumonia><COVID-19 virus><COVID19><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><CV19><Calcium><Calcium Channel><Calcium Channel Antagonist Receptor><Calcium Channel Blocker Receptors><Calcium Ion Channels><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Clinical Data><Clinical Trials><Clinical Trials Design><CoV-2><CoV2><Coronaviridae><Coronavirus><Da Nang Lung><Data><Data Science><Disease><Disorder><Dose><Enrollment><Envelope Protein><Feedback><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><Generations><Goals><Heterogeneity><Human><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Immune Cell Activation><Immunology><In Vitro><Infection><Inflammasome><Inflammation><Inflammatory><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Interruption><Intracellular Communication and Signaling><Investigators><Liquid substance><Lung><Lung Inflammation><Lung Respiratory System><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Measures><Mechanical ventilation><Mediating><Minority><Modern Man><Mφ><Nature><Patients><Pharmacology><Pneumonia><Pneumonitis><Preinterleukin 1 Beta><Production><Public Health><Publications><Pulmonary Inflammation><Pulmonary Macrophages><Research Personnel><Researchers><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated pneumonia><SARS-CoV-2 induced pneumonia><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 pneumonia><SARS-CoV-2 positive patient><SARS-CoV-2 related pneumonia><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><Scientific Publication><Secondary to><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Shock Lung><Signal Transduction><Signal Transduction Systems><Signaling><Stiff lung><T memory cell><T-Cell Activation><T-Cells><T-Lymphocyte><Testing><Tissues><VDCC><Virus><Voltage-Dependent Calcium Channels><Wuhan coronavirus><accessory cell><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after severe acute respiratory distress syndrome CoV-2 infection><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiinflammatory><antiviral compound><antiviral medication><antiviral therapeutic><bio-markers><biologic><biologic marker><biological signal transduction><biomarker><computer based prediction><corona virus><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 associated pneumonia><coronavirus disease 2019 induced pneumonia><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 pneumonia><coronavirus disease 2019 positive patient><coronavirus disease 2019 related pneumonia><coronavirus disease 2019 virus><coronavirus disease associated pneumonia><coronavirus disease induced pneumonia><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease pneumonia><coronavirus disease positive patient><coronavirus disease related pneumonia><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 pneumonia><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cross reactivity><cytokine><disease severity><enroll><env Antigens><env Gene Products><env Polyproteins><env Protein><epithelial repair><flow cytophotometry><fluid><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following severe acute respiratory distress syndrome CoV-2 infection><genomic data><genomic data-set><genomic dataset><hCoV19><human disease><human tissue><immune activation><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><inhibitor><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><liquid><lymph gland><lymph nodes><lymphnodes><macrophage><mechanical respiratory assist><mechanically ventilated><memory T lymphocyte><model of animal><model organism><mutant><nCoV2><novel><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 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><post SARS-CoV-2 infection><prediction model><predictive modeling><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><pulmonary><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 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 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><small molecule><small molecule inhibitor><social role><stem><systemic inflammation><systemic inflammatory response><thymus derived lymphocyte><transcriptomics><virology><wet lung>