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Principal Investigator: Monica Kraft
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2022
Award: $1,431,641
Funding agency: National Institute of Allergy and Infectious Diseases
In this AADCRC program renewal, we will focus on three critical and understudied innate immune factors
and how they impact viral infections in asthma: the anionic phospholipids of surfactant (palmitoyl-
oleoyl-phosphatidylglycerol, POPG, and phosphatidylinositol, PI), Toll interacting protein (Tollip), and
surfactant protein-A (SP-A). Because these mediators have complementary functions to modulate
inflammation and immunity in asthma and infection, we propose three interrelated, synergistic, self-standing
projects to investigate how these mediators orchestrate novel innate immune responses associated with viral
infections in asthma. We will study three viruses with a spectrum of effects in airway disease, and
determine how innate responses protect against them. Specifically, we will focus on rhinovirus C (RV-C), a
known exacerbator of asthma that can cause severe disease; influenza A, a virus whose effect in asthma remains
ambiguous and SARS-CoV-2, a virus that can cause severe lung disease, but for which asthma may not be a
risk factor, and may in fact confer protection. We show innovative preliminary data indicating that 1) POPG, PI
and SP-A attenuate RV-C infection; 2) Tollip exhibits protective effects as it is required for IL-13 to generate
soluble ST2 that in turn attenuates the effects of IL-33 during influenza A infection; and 3) SP-A and type 2
cytokines confer protection in the effector and initiation phases of SARS-CoV-2 infection in asthma by inhibiting
the expression and function of ACE2, the SARS-CoV-2 receptor, through effects upon transcription, receptor
binding and downstream pro-inflammatory signaling. Thus, all these innate immune components appear to
protect against viral infections in asthma. Our exciting preliminary data underpin our program’s overall
hypothesis that POPG/PI, Tollip and SP-A function as unique immune modulators that attenuate the
impact of specific viral infections (RV-C, Influenza A and SARS-CoV-2) in type-2 asthma. Therefore,
supplementation of functional POPG/PI, SP-A and the IL-33 decoy receptor sST2 may be novel strategies
against asthma exacerbations due to viral infections. Project 1 will critically test the activity of POPG/PI and SP-
A supplementation as a novel molecular tool for disrupting infections due to RV-C, a virus known to exacerbate
asthma. Project 2 will determine how Tollip protects against viral exacerbations caused by influenza A in asthma
through inhibition of IL-33 signaling. Project 3 will determine how type-2 cytokines and SP-A synergize to protect
against SARS-CoV-2 infection through inhibition of ACE2-mediated infection and IL-6 signaling pathways. We
also include an Administrative Core and a Clinical Core, both which serve all projects equally. We build upon
productive collaborations of over 20 years on innate molecular mechanisms underlying the interaction between
type 2 inflammation and viral exacerbations of asthma. The strong synergy among our three projects will
accelerate progress toward novel therapies by demonstrating that the innate immune components under
study protect against viral infection in asthma.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Airway Disease><Allergens><Allergic Disease><Alveolar><Asthma><Atopic Allergy><Attenuated><Autoregulation><Body Tissues><Bronchial Asthma><Bronchoscopy><COVID-19 infection><COVID-19 virus><COVID19 infection><COVID19 virus><Cell Communication and Signaling><Cell Signaling><Chronic><Clinical><CoV-2><CoV2><Collaborations><Communication><Data><Disease><Disorder><Distal><Epithelial Cells><Event><Exhibits><Gene Transcription><Genetic Transcription><Genotype><Glycerol Phosphoglycerides><Grippe><Homeostasis><House Dust Mites><Housedust Mites><Human><IL 6 signaling pathway><IL-13><IL13><IL6 Signaling Pathway><IMiD><Immune><Immune modulatory therapeutic><Immune response><Immunes><Immunity><Immunologic Factors><Immunological Factors><Immunological response><Immunomodulators><In Vitro><Infection><Infectious Agent><Inflammation><Inflammatory><Influenza><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Innate Immune Response><Innate Immunity><Inositide Phospholipids><Inositol Phosphoglycerides><Inositol Phospholipids><Interleukin-13><Intracellular Communication and Signaling><Irritants><Lung diseases><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Nasal><Nasal Passages Nose><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Nose><Orthomyxovirus Type A><Participant><Pathway interactions><Phase><Phenotype><Phosphatides><Phosphatidyl Inositol><Phosphatidylglycerols><Phosphatidylinositols><Phosphoinositides><Phospholipids><Physiologic><Physiological><Physiological Homeostasis><Position><Positioning Attribute><Production><Productivity><PtdIns><Pulmonary Body System><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Organ System><Pulmonary Surfactant-Associated Protein A><Pyroglyphidae><RNA Expression><Receptor Protein><Research><Research Resources><Resources><Respiratory System><Respiratory System, Nose, Nasal Passages><Respiratory Tracts><Respiratory tract structure><Rhinovirus><Risk Factors><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><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><SP-A Protein><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 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><Severities><Shipping><Signal Transduction><Signal Transduction Systems><Signaling><Supplementation><Surfactant Protein A><TOLLIP><TOLLIP gene><Testing><Tissues><Toll-Interacting Protein><Transcription><Type A Influenza><Viral><Viral Diseases><Virus><Virus Diseases><Work><Wuhan coronavirus><angiotensin converting enzyme 2><angiotensin converting enzyme II><asthma attack><asthma exacerbation><atopic triad><atopy><base><biological signal transduction><bronchial epithelium><clinical relevance><clinically relevant><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine><data management><disease of the lung><disorder of the lung><exacerbation in asthma><exacerbation prone asthma><exacerbation prone asthmatic><hCoV19><host response><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulators><immune modulatory agents><immune modulatory drugs><immune system response><immunologic substance><immunological substance><immunomodulating agents><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoresponse><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><infectious organism><innate immune function><innovate><innovation><innovative><lung disorder><nCoV2><new approaches><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel strategies><novel strategy><novel therapeutics><novel therapy><pathway><phosphatidyl glycerol><programs><protective effect><receptor><receptor binding><receptor bound><recruit><response><social role><surfactant><synergism><tool><viral infection><virus infection><virus-induced disease>