Document text
Principal Investigator: Kari Ann Shirey
Organization: UNIVERSITY OF MARYLAND BALTIMORE
Fiscal Year: 2021
Award: $231,750
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
Influenza is a highly contagious respiratory illness that the CDC has estimated to afflict ~47.5 million
Americans with up to 62,00 deaths from October 1, 2019 to April 4, 2020. In the absence of a “universal
influenza vaccine,” yearly vaccination is strongly recommended; however, the composition of each vaccine is
based on predictions of which strains will predominate in the following year and such predictions may be
incorrect. Approved antivirals can ameliorate disease by limiting viral replication, but they must be administered
early in infection to be effective, and resistant influenza strains have emerged. While influenza-induced disease
is initiated by viral replication resulting in airway epithelial damage, the severe inflammatory response that
follows as a result of metabolic stress in innate immune cells (e.g., macrophages) ultimately elicits a “cytokine
storm” that may lead to acute respiratory distress syndrome (ARDS) and death. Thus, a new approach that
targets the host innate immune response would represent a highly significant therapeutic advance for influenza
as well as other respiratory viruses that lead to ARDS, e.g., SARS-CoV-2. We have identified Toll-like receptor
4 (TLR4), a pattern recognition receptor best known for its ability to sense Gram-negative lipopolysaccharide
(LPS), as key to the host inflammatory response to influenza. This was initially surprising since influenza virus
does not express any “pathogen-associated molecular patterns” that trigger inflammation via TLR4.
Nonetheless, using both TLR4-/- mice and multiple TLR4 antagonists in both a mouse model of influenza
infection, as well as in cotton rats (Sigmodon hispidus; CR) that are susceptible to non-adapted strains of
human influenza, we rigorously demonstrated that TLR4 signaling is central to the generation of lung and
systemic inflammation in response to infection. We identified a host-derived protein, High Mobility Group Box-1
(HMGB1), released from dying cells during infection, that acts as a “danger-associated molecular pattern,”
thereby triggering TLR4 through its co-receptor, MD2. Recently, we identified a second host-derived protein,
gastrin-releasing peptide (GRP), as contributory to influenza-mediated disease, using three distinct inhibitors of
GRP or GRP receptor signaling to significantly blunt cytokine production, lung pathology, and lethality when
administered to mice therapeutically. Our published and preliminary data support the central hypothesis that
these two mediators are interrelated and converge during the host response to influenza infection. In two
Specific Aims, we propose to (1) delineate influenza-mediated interactions between GRP receptor (GRPR)-
and TLR4/MD2-mediated signaling, and (2) correlate GRP and HMGB1 levels with disease severity in two
distinct experimental models of influenza-induced disease and in influenza-infected patients. In this exploratory
R21 application, we shall seek to identify the mechanistic underpinnings of the relationship between these two
signaling pathways with the potential of identifying therapeutic strategies to ameliorate disease.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><ARDS><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Acute respiratory infection><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Agonist><American><Aminalon><Aminalone><Amphoterin><Animal Model><Animal Models and Related Studies><Antiviral Agents><Antiviral Drugs><Antivirals><BB2><Bacterial Infections><Biological Markers><Blood Circulation><Blood Serum><Blood monocyte><Bloodstream><Bombesin Receptor><CD54><CDC><COVID-19 virus><COVID19 virus><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cells><Centers for Disease Control><Centers for Disease Control and Prevention><Centers for Disease Control and Prevention (U.S.)><Cessation of life><Chromatin><Chromosomal Protein, Nonhistone, HMG1><Circulation><Clinical><CoV-2><CoV2><Cotton Rats><Cytokine Gene><D pneumoniae><D. pneumoniae><Da Nang Lung><Data><Death><Diplococcus pneumoniae><Disease><Disease Outbreaks><Disorder><Epithelial Cells><Experimental Models><FM1 Gene Product><GABA><GRP><GRP gene><Gastrin releasing peptide><Gastrin-Releasing Peptide Receptors><Gene Expression><Generations><Goals><Grippe><H1N1><H1N1 Virus><HMG-1><HMG-1 Protein><HMG1><HMG3><HMGB1 Protein><Heparin-Binding Protein p30><High Mobility Group Box Protein 1><High Mobility Group Protein 1><High-Mobility Group (Nonhistone Chromosomal) Protein 1><High-Mobility Group Box 1><Histopathology><Homolog of Drosophila TOLL><Human><ICAM-1 Gene><ICAM1><ICAM1 gene><Immune><Immune response><Immunes><Immunity><Immunological response><Infection><Infiltration><Inflammation><Inflammatory Response><Influenza><Influenza A Virus, H1N1 Subtype><Influenza Virus><Innate Immune Response><Intracellular Communication and Signaling><Lead><Lipopolysaccharides><Lung><Lung Inflammation><Lung Respiratory System><MRSA><Marrow monocyte><Measures><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Messenger RNA><Metabolic stress><Methicillin Resistant S Aureus><Methicillin Resistant S. Aureus><Mice><Mice Mammals><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Mφ><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuroendocrine><Neuroendocrine System><Neuromedin B Receptors><Neurons><Neurosecretory Systems><Nonhistone Chromosomal Protein HGM1><Outbreaks><Oxidative Stress><Pathology><Pathway interactions><Patients><Pattern><Pattern recognition receptor><Pb element><Play><Pneumococcus><Process><Production><Proteins><Publishing><Pulmonary Pathology><Reagent><Receptor Protein><Regulation><Reporting><Resistance><Rodent Model><Role><S pneumoniae><S. pneumoniae><SARS corona virus 2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SBP-1><SRP receptor><Secondary to><Sepsis><Serum><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><Severity of illness><Shock Lung><Sigmodon><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stiff lung><Streptococcus pneumoniae><Sulfoglucuronyl Carbohydrate Binding Protein><Symptoms><TLR4><TLR4 gene><Techniques><Testing><Therapeutic><Toll Homologue><United States Centers for Disease Control><United States Centers for Disease Control and Prevention><Vaccination><Vaccines><Virus><Virus Replication><Wuhan coronavirus><age group><airway epithelium><anti-viral agents><anti-viral drugs><anti-viral efficacy><anti-virals><antiviral efficacy><bacteria infection><bacterial disease><base><bio-markers><biologic marker><biological signal transduction><biomarker><blood infection><bloodstream infection><c new><child patients><coronavirus disease 2019 virus><cytokine><cytokine release syndrome><cytokine storm><disease severity><flu infection><flu serotype><flu strain><flu subtype><flu viral strain><flu virus infection><flu virus strain><gamma-Aminobutyric Acid><gastrin inhibitor><global health><hCoV19><heavy metal Pb><heavy metal lead><host response><human disease><immune system response><immunoresponse><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza serotype><influenza strain><influenza subtype><influenza viral strain><influenza virus infection><influenza virus strain><influenzavirus><inhibitor><inhibitor/antagonist><lung pathogen><lung pathology><mRNA><macrophage><mammalian bombesin><methicillin resistant Staphylococcus aureus><methicillin-resistant S. aureus><model of animal><model organism><monocyte><mortality><mouse Tlr-4 protein><mouse Tlr4 protein><mouse model><mouse toll-like receptor 4><murine model><nCoV2><necrocytosis><neuronal><new approaches><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel approaches><novel drug treatments><novel drugs><novel strategies><novel strategy><novel therapeutics><novel therapy><pandemic><pandemic disease><pathogen><pathway><pediatric patients><protein expression><pulmonary><pulmonary pathogen><receptor><receptor expression><resistant><respiratory><respiratory pathogen><respiratory virus><response><secondary infection><signal peptide receptor><signal recognition particle receptor><social role><systemic inflammation><systemic inflammatory response><targeted biomarker><therapeutic target><toll-like receptor 4><universal flu vaccine><universal influenza vaccine><universal influenza virus vaccine><universal vaccine against flu><universal vaccine against influenza><viral multiplication><viral replication><virus multiplication><wet lung><γ-Aminobutyric Acid>