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Principal Investigator: Monica Kraft
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2021
Award: $371,166
Funding agency: National Institute of Allergy and Infectious Diseases
During the first cycle of our AADCRC program, our project focused primarily on Surfactant Protein A (SP-A), a
known innate immune modulator that exhibits important anti-inflammatory effects in asthma. In this renewal, we
show preliminary data that SP-A binds the interleukin (IL)-6 receptor and disrupts IL-6 signaling, events relevant
to specific asthma phenotypes. While this work was progressing, the Severe Acute Respiratory Syndrome-
related Coronavirus 2 (SARS-CoV-2)-driven coronavirus disease 2019 (COVID-19) pandemic emerged and has
fundamentally changed our world. Elevated serum IL-6 is a hallmark of the “cytokine storm” associated with
severe COVID-19 acute respiratory distress and IL-6 inhibitors show promise as treatments. Our data suggest
that SP-A exhibits innate functions relevant to SARS-CoV-2 infection by inhibiting IL-6 signaling intermediates
and also by binding to angiotensin converting enzyme-2 (ACE2), the receptor used by SARS-CoV-2 for entry
into host cells. These findings suggest that SP-A may attenuate the inappropriate innate immune responses
in COVID-19 and by this mechanism, could play a role in the treatment of SARS-CoV-2 infection. Several
chronic lung-based comorbidities have been shown to increase the severity and mortality associated with
COVID-19 - with the notable exception of asthma. Evidence from our group suggests that type-2 (T2) cytokines
such as IL-4 and IL-13, which are critical molecular underpinnings of atopic asthma, reduce ACE2 expression in
airway epithelial cells from T2 asthma. These findings suggest that atopic asthma-associated T2 cytokines
protect against COVID-19 by modulating infection. In this AADCRC renewal, we will build on these
preliminary data and merge two complementary, unique lines of investigation to expand the focus of our proposal
and investigate the interplay of SP-A and T2 cytokines at both the initiation and the effector stages of SARS-
CoV-2 respiratory tract infection in asthma. We will test the novel hypothesis that SP-A effectively limits COVID-
19 by decreasing ACE2-mediated events through direct receptor binding and inhibition of IL-6 signaling
pathways. In the setting of atopic asthma, type-2 cytokines may reduce the susceptibility to SARS-CoV-
2 infection by inhibiting ACE2 expression and function. In aim 1, we will determine the impact of SP-A in
limiting SARS-CoV-2 infection of human nasal, bronchial and distal airway epithelial cells and whether these
effects depend upon ACE2 binding and modulation of IL-6 signaling. In aim 2, we will assess ACE2 expression
in nasal, bronchial and distal epithelial cells from normal atopic and non-atopic controls and T2 asthmatic
participants, and determine how T2 cytokines and virus-induced interferons interact to regulate epithelial cell
ACE2 expression and SARS-CoV-2 infection in these cells. We hypothesize that SP-A and T2 cytokines can
synergize to dampen both the initiation and the effector phases of SARS-CoV-2 infection, thereby protecting
from COVID-19. This proposal leverages expertise in asthma, SP-A immune responses, virology and epithelial
biology within the project and synergizes well with Projects 1 and 2 to better understand viral insults in asthma.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><ARDS><Actemra><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Allergic asthma><Antiinflammatory Effect><Asthma><Attenuated><B cell differentiation factor><B cell growth factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-1><B-Cell Differentiation Factor-2><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><B-Cell Stimulatory Factor-2><BCDF><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF-2><BSF1><BSF2><Binding><Binetrakin><Biology><Blood Serum><Bronchial Asthma><CD126 Antigens><CD126 Receptor><COPD><COVID><COVID crisis><COVID disease severity><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID severity><COVID-19><COVID-19 crisis><COVID-19 disease severity><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 severity><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID19><COVID19 crisis><COVID19 disease severity><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 severity><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemotactic Cytokines><Chronic><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Airway Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><CoV disease><CoV-2><CoV2><Collagenous Lectins><Collectins><Communities><Country><Da Nang Lung><Data><Distal><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Epithelial><Epithelial Cells><Event><Exhibits><Extrinsic asthma><Family><Gene Transcription><Genetic Transcription><Grippe><HPGF><Hepatocyte-Stimulating Factor><Homologous Chemotactic Cytokines><Human><Hybridoma Growth Factor><IFN><IFN-beta 2><IFNB2><IL-13><IL-4><IL-6><IL-6 Receptors><IL-6 inhibitor><IL13><IL4 Protein><IL6 Protein><IL6 Receptors><IL6 inhibitor><IMiD><Immune modulatory therapeutic><Immune response><Immunological response><Immunomodulators><Infection><Inflammation Mediators><Inflammatory Response><Influenza><Innate Immune Response><Innate Immunity><Intercrines><Interferons><Interleukin 6 Receptor><Interleukin-13><Interleukin-4><Interleukin-4 Precursor><Interleukin-6><Interleukin-6 inhibitor><Intracellular Communication and Signaling><Investigation><Lymphocyte Stimulatory Factor 1><MCGF-2><MGI-2><Mast Cell Growth Factor-2><Mediating><Modeling><Modern Man><Molecular><Molecular Interaction><Myeloid Differentiation-Inducing Protein><Nasal><Nasal Passages Nose><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Nose><Participant><Pathogenesis><Phase><Phenotype><Plasmacytoma Growth Factor><Play><Predisposition><Preparation><Pulmonary Surfactant-Associated Protein A><RNA Expression><Receptor Inhibition><Receptor Protein><Research><Respiratory Infections><Respiratory System, Nose, Nasal Passages><Respiratory Tract Infections><Role><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 disease severity><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 severity><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 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coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Severities><Shock Lung><Sight><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stiff lung><Surfactant Protein A><Susceptibility><T-Cell Growth Factor 2><Testing><Transcription><Type II Pneumocyte><Viral><Viral Diseases><Virus><Virus Diseases><Vision><Work><Wuhan coronavirus><airway epithelium><alveolar type II cell><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-inflammatory effect><asthmatic><atopic asthma><biological signal transduction><cell type><chemoattractant cytokine><chemokine><co-morbid><co-morbidity><comorbidity><corona virus disease><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 disease severity><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health 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