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Principal Investigator: Emanuela Marina Bruscia
Organization: YALE UNIVERSITY
Fiscal Year: 2022
Award: $632,310
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Macrophages (MΦs) kill microorganisms, engulf dead cells and debris, and regulate the immune response. They
are thus gatekeepers of tissue health, including the lungs. The lung-tissue-resident MΦs (TR-MΦs) are the
interstitial and alveolar MΦs, which have complementary but distinct functions. In response to infections, lungs
are rapidly populated by waves of Ly6C+ circulating monocytes. In concert with TR-MΦs, these monocytes fight
the infection, then facilitate the resolution of the inflammatory response. Many chronic lung inflammatory
diseases, including cystic fibrosis (CF), are associated with dysregulated MΦ function. Our long- term goal is to
understand how different lung MΦ populations contribute to lung hyper-inflammation and infection and to
elucidate the biology of these distinct cell populations. The objective of this proposal is to characterize ezrin’s
role in monocyte/MΦ function. Our central hypothesis is that ezrin controls monocyte/MΦ cortical actin
organization and signal transduction events in response to inflammatory/infectious stimuli. These cellular
changes allow the MΦs to spread, move, phagocytize, and survive, thus shaping the magnitude and quality of
the lung immune response to infections. The rationale for these studies is that low ezrin levels have been found
in MΦs from patients with CF (our work). Other investigators have also reported low ezrin levels in blood cells
from individuals with asthma. Thus, by elucidating the molecular mechanism by which ezrin shapes lung MΦ
functions, we could identify potential therapeutic targets for lung diseases. Our specific aims will test the following
hypotheses: (Aim 1) ezrin is required for the signaling that drives MΦs to adhere to the lung extracellular matrix
and to differentiate in response to LPS; (Aim 2) ezrin is needed for efficient phagocytosis of Staphylococcus
aureus and Pseudomonas aeruginosa, two microorganisms that CF patients fail to efficiently eradicate from their
lungs; (Aim 3) the acquired “cellular ezrin low-state” inactivated CF MΦs is central to their uncontrolled immune
signaling and reduced phagocytosis. The contribution is significant since very little is known about ezrin’s role in
regulating lung MΦ activation. Our proposed research is innovative because we will use an unprecedented
mouse model in which ezrin is knocked out in monocytes and MΦs. Thus, the proposed studies will investigate in
depth the consequences of ezrin loss in monocytes and MΦs during lung infection and inflammation.
Terms: <Actin-Binding Protein><Actins><Adhesions><Affect><Airway infections><Alveolar><Asthma><Bacteria><Bacterial Infections><Binding><Biology><Blood Cells><Blood monocyte><Body Tissues><Bronchial Asthma><CF lung disease><CF mice><CF mouse model><CF patients><CFTR><CFTR Protein><COPD><Ca2+-Activated Protease><Calcium-Activated Neutral Protease><Calcium-Activated Neutral Proteinase><Calcium-Activated Protease><Calcium-Dependent Neutral Protease><Calcium-Dependent Neutral Proteinase><Calpain><Cell Adhesion><Cell Body><Cell Communication and Signaling><Cell Function><Cell Process><Cell Signaling><Cell membrane><Cell physiology><Cell-Extracellular Matrix><Cells><Cellular Adhesion><Cellular Function><Cellular Immune Function><Cellular Matrix><Cellular Physiology><Cellular Process><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Cystic Fibrosis><Cystic Fibrosis Transmembrane Conductance Regulator><Cytoplasmic Membrane><Cytoskeletal System><Cytoskeleton><Data><Desminase><Disease><Disorder><Dysfunction><ECM><Event><Extracellular Matrix><Failure><Functional disorder><Gatekeeping><Goals><Health><Host Defense><IgG Receptors><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immune signaling><Immunodeficiency and Immunosuppression Disorders><Immunoglobulin G Receptor><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunomodulation><Impairment><Individual><Infection><Inflammation><Inflammatory><Inflammatory Response><Integrins><Integrins Extracellular Matrix><Intracellular Communication and Signaling><Investigators><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Lipopolysaccharides><Lung><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung diseases><Lung immune response><Lung infections><Marrow monocyte><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mice><Mice Mammals><Modeling><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Mucous body substance><Mucoviscidosis><Mucus><Murine><Mus><Mφ><Null Mouse><Obstruction><P aeruginosa><P. aeruginosa><PI-3K/AKT><PI3K/AKT><Papain-Like Cysteine Protease><Pathologic><Pathway interactions><Peripheral Blood Cell><Phagocytes><Phagocytic Cell><Phagocytosis><Physiopathology><Plasma Membrane><Pneumonitis><Population><Protein Family><Pseudomonas aeruginosa><Pseudomonas pyocyanea><Publishing><Pulmonary Cystic Fibrosis><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Inflammation><Reporting><Research><Research Personnel><Researchers><Resolution><Respiratory Infections><Respiratory Tract Infections><Role><S aureus><S. aureus><Severity of illness><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Staph aureus><Staphylococcus aureus><Stimulus><Structure of parenchyma of lung><Subcellular Process><Surface Proteins><Testing><Tissues><Work><amebocyte><bacteria infection><bacterial disease><bactericidal><bactericide><base><biological signal transduction><cell cortex><chronic inflammatory lung disease><cystic fibrosis lung><cystic fibrosis lung disease><cystic fibrosis mouse><cystic fibrosis mouse model><cystic fibrosis patients><cystic fibrosis transmembrane regulator><disease of the lung><disease severity><disorder of the lung><ezrin><fighting><gamma Fc Receptors><gatekeeper><host response><immune function><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><in vivo Model><individuals with CF><individuals with cystic fibrosis><innovate><innovation><innovative><interstitial><intracellular skeleton><lung disorder><macrophage><member><membrane-organizing extension spike protein><microorganism><moesin><monocyte><mortality><mouse model><mucous><murine model><particle><pathogen><pathophysiology><pathway><patients with CF><patients with cystic fibrosis><phosphoprotein p81><plasmalemma><pulmonary><pulmonary immune response><pulmonary infections><radixin><radixin protein><recruit><response><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target>