Project 1: Vimentin regulates host response and repair mechanisms to influenza A viral pneumonia

NIH Pandemic-Era Grants

Pandemic Era Grants

2021

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Principal Investigator: KAREN M RIDGE
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2021
Award: $539,501
Funding agency: National Heart Lung and Blood Institute

PROJECT SUMMARY PROJECT 1
Severe viral pneumonia, due to influenza A virus (IAV) damages the lower respiratory tract to cause acute
respiratory distress syndrome (ARDS). The persistence of respiratory failure in patients with ARDS is a
consequence of persistent inflammation and the failure of normal mechanisms of inflammation resolution and
lung tissue repair. A crucial step in the immune response to IAV is the activation of the NLRP3 inflammasome
and subsequent secretion of inflammatory cytokines, IL-1β and IL-18.
Vimentin regulates the formation and activation of the NLRP3 inflammasome. We propose to modulate the NLRP3 inflammasome by temporally deleting vimentin in monocyte-derived alveolar macrophages (MoAMs) post-viral clearance in IAV-infected mice.
MoAMs play crucial roles in both initiation and continuation of the immune response, limiting repair of the injured
lung tissue. Our data revealed that genes driving the inflammatory phenotype are suppressed in Vimentin−/−
MoAMs. Using novel lineage-tracing techniques in inducible conditional knockout mice, we will investigate
whether vimentin regulates persistent inflammation by promoting an inflammatory phenotype in MoAMs following
clearance of IAV. Regulatory T cells also contribute to recovery from viral pneumonia by suppressing immune
responses and promoting lung tissue repair. Our data suggest that Vimentin−/− Treg cells exhibit a cell-
autonomous increase in their pro-repair function following IAV infection. We hypothesize that a targeted loss
of vimentin in alveolar macrophages and regulatory T cells is required to promote pro-repair processes
following severe IAV infection.
Specific Aim 1. To determine whether a targeted loss of vimentin in monocyte-derived alveolar
macrophages suppresses their inflammatory response and promotes lung repair following severe
influenza infection. We propose to disrupt the persistent inflammation that limits repair of injured lung tissue by
temporally-controlled deletion of vimentin in monocyte-derived alveolar macrophages post-viral clearance in IAV-
infected mice.
Specific Aim 2. To determine whether depolymerization of vimentin intermediate filaments causes
metabolic reprogramming to suppress alveolar macrophage inflammatory phenotype. Our preliminary
data suggest that a switch from inflammatory to pro-repair macrophage phenotype is associated with metabolic
reprogramming and depolymerization of vimentin intermediate filaments.
Specific Aim 3. To determine whether temporal, cell-specific loss of vimentin augments the pro-repair
function of regulatory T cells during recovery from IAV-induced pneumonia. We propose to determine
whether Vimentin−/− Treg cells exhibit their augmented cell-autonomous pro-repair function via increased
adenosine signaling and amphiregulin production following influenza A virus infection.

Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ARDS><Acute><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adenosine><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Alveolar Macrophages><Amphiregulin><Anthelone U><Antibodies><Automobile Driving><Beta Proprotein Interleukin 1><Blood monocyte><Body Tissues><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 patient><COVID-19 pneumonia><COVID-19 positive patient><COVID-19 related pneumonia><COVID-19 virus><COVID19><COVID19 patient><COVID19 positive patient><COVID19 virus><CRGF><CV-19><CV19><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemotactic Cytokines><Clinical><Clinical Treatment Moab><CoV-2><CoV2><Colorectum Cell-Derived Growth Factor><Da Nang Lung><Data><Enrollment><Epidermal Growth Factor><Epidermal Growth Factor-Urogastrone><Epithelial><Etiology><Exhibits><Expression Signature><Failure><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Funding><Funding Opportunities><Gene Expression><Gene Expression Profile><Genes><Homologous Chemotactic Cytokines><IFN-gamma-Inducing Factor><IGIF><IL-1 Gamma><IL-1 beta><IL-1 β><IL-1-b><IL-18><IL-1g><IL-1β><IL1-Beta><IL1-β><IL18 Protein><IL1B Protein><IL1F2><IL1F4><IL1β><Immune response><Immunological response><Impairment><Infection><Inflammasome><Inflammation><Inflammatory><Inflammatory Response><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Instruction><Intercrines><Interferon-gamma-Inducing Factor><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 Proprotein><Interleukin 1beta><Interleukin-1 Gamma><Interleukin-1 beta><Interleukin-18><Interleukin-18 Precursor><Interleukin-1β><Intermediate Filaments><Intracellular Communication and Signaling><KO mice><Keratinocyte-Derived Autocrine Factor><Knock-out Mice><Knockout Mice><Lower respiratory tract structure><Lung><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><MGC12320><Marrow monocyte><Mediating><Metabolic><Mice><Mice Mammals><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Murine><Mus><Mφ><NIAID><National Institute of Allergy and Infectious Disease><Null Mouse><Orthomyxovirus Type A><Outcome><Patients><Phenotype><Play><Pneumonia><Preinterleukin 1 Beta><Process><Production><Pulmonary Macrophages><Recovery><Regulatory T-Lymphocyte><Reporting><Research><Resolution><Respiratory Failure><Role><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 associated pneumonia><SARS-CoV-2 induced pneumonia><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 pneumonia><SARS-CoV-2 positive patient><SARS-CoV-2 related pneumonia><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Schwannoma-Derived Growth Factor><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 related corona virus 2><Shock Lung><Signal Transduction><Signal Transduction Systems><Signaling><Stiff lung><Structure of parenchyma of lung><Techniques><Testing><Tissues><Treg><Type A Influenza><Urogastrone><Vimentin><Viral><Viral Diseases><Viral Pneumonia><Virus><Virus Diseases><Wuhan coronavirus><beta-Urogastrone><biological signal transduction><causation><chemoattractant cytokine><chemokine><clinical relevance><clinically relevant><colorectal cell-derived growth factor><colorectal-associated growth factor><colorectum-associated growth factor><community acquired pneumonia><community associated pneumonia><conditional knock-out><conditional knockout><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 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 patient><cytokine><depolymerization><disease causation><driving><enroll><experiment><experimental research><experimental study><extracellular><flow cytophotometry><flu infection><flu virus infection><gene expression pattern><gene expression signature><hCoV19><host response><immune system response><immunoresponse><improved><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><injury and repair><keratinocyte autocrine factor><lower respiratory tract><lung failure><lung injury><lung repair><mAbs><macrophage><monocyte><mortality><mouse model><murine model><nCoV2><novel><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><placebo controlled trial><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><prevent><preventing><pulmonary><pulmonary failure><pulmonary repair><recruit><regulatory T-cells><repair><repair function><repaired><reparative function><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><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tissue repair><transcriptional profile><transcriptional signature><viral infection><virus infection><virus-induced disease><wet lung>