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Principal Investigator: Jay R Radke
Organization: BOISE VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Over 25% of US Veterans have diabetes, and those Veterans are at an increased risk of hospitalization
and increased morbidity/mortality following severe respiratory viral infections, such as, influenza (H1N1), SARS-
CoV-2 (COVID) and adenovirus (Ad). Infection with these respiratory viruses causes acute lung injury (ALI) that
can result in acute respiratory distress syndrome (ARDS), with a mortality rate of ~40%. There are few
therapeutic options for ALI/ARDS. Virus induced ALI/ARDS is driven primarily by uncontrolled inflammatory
responses. Alveolar macrophages both induce and resolve ALI/ARDS, based on their polarization/inflammatory
state. The plasticity of macrophages to vary between pro-inflammatory (M1, pro-ALI/ARDS) and anti-
inflammatory (M2, anti-ALI/ARDS) phenotypes is driven by their metabolic states. Diabetes is a metabolic
disorder in which levels of blood glucose are high and glycolysis is the preferred cellular metabolic pathway.
Macrophages from diabetic patients have a high rate of glycolysis and an increased M1 phenotype. In addition,
macrophages from diabetic patients have a lower rate of plasticity to change from M1 to M2 because of this shift
to glycolysis. One possibility is that this glycolytic shift contributes to severe outcomes from respiratory viral
infections in diabetic patients.
The Syrian hamster is naturally permissive for influenza, SARS-CoV-2 and Ad (in contrast to other
rodents that require viral adaptation). In addition, the Syrian hamster can naturally become diabetic with a high
fat/high sugar diet. Ad14p1 is an emergent strain of Ad14 that has caused outbreaks of severe respiratory illness
and ALI/ARDS throughout the world. Hamster infection with Ad14p1 results in a patchy bronchopneumonia, as
seen in other severe human viral respiratory infections. In contrast, the prototype strain of Ad14 induces little
lung inflammation. Other studies have shown that cells dying from Ad14 infection induce an M2-like human
macrophage response, while cells dying from Ad14p1 infection fail to change M1 alveolar macrophages to an
M2 phenotype. This dying infected cell activity is regulated by the expression of the Ad gene, E1B 20K. Cells
infected by Ad14 produced sufficient E1B 20K to repolarize M1 macrophages to M2, while Ad14p1 infection does
not produce sufficient E1B 20K, and the infected cells fail to alter M1 macrophage polarization. Therefore, the
hamster model of Ad14p1 ALI/ARDS provides an appropriate system to study how diabetes affects macrophage
polarization and pathogenesis during severe viral respiratory infections. The long-term goal of this project is to
understand how emergent viruses regulate macrophage polarization to develop novel therapeutic strategies to
drive macrophage polarization to an ALI/ARDS resolving phenotype in both diabetic and non-diabetic Veterans.
To achieve this goal, a multi-omics approach will be used to identify and phenotype macrophages in
normal and diabetic hamsters infected with Ad14p1. Transcriptomics using single-cell RNA sequencing will use
gene expression profiles at the resolution of individual cells to identify and phenotype macrophages and their
polarization states. Infiltrating immune cells and other lung resident cells will also be identified. Proteomics will
be used to identify cytokines and chemokines that drive Ad14p1 pathogenesis. Metabolomics will be used to
understand the unique metabolic changes in the lungs during Ad14p1 infection in diabetes and how those
changes affect macrophage polarization. Comparative virology studies with infection of normal and diabetic
hamsters with a pandemic strain of H1N1 influenza will be used to determine whether similar mechanisms of
pathogenesis are involved in ALI/ARDS pathogenesis induced by other severe respiratory viruses. Finally, we
will test the role of miRNA expression during prototype Ad14 and Ad14p1 infection in regulating macrophage
polarization and pathogenesis, with the goals of defining mechanisms of immunomodulation and identifying
candidate miRNAs that might be used as therapeutic agents against viral ALI/ARDS.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ARDS><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adenoviridae><Adenovirus Protein><Adenoviruses><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Adult-Onset Diabetes Mellitus><Affect><Alveolar Macrophages><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Blood Glucose><Blood Sugar><Bronchopneumonia><COVID disease severity><COVID severity><COVID-19><COVID-19 disease severity><COVID-19 infection><COVID-19 severity><COVID-19 virus><COVID-19 virus infection><COVID19 disease severity><COVID19 infection><COVID19 severity><COVID19 virus><CV-19><Causality><Cell Body><Cells><Cellular Regulation><Cessation of life><Chemotactic Cytokines><Clinical><CoV-2><CoV2><Communicable Diseases><Comparative Study><Coronavirus Infectious Disease 2019><Cricetinae><Da Nang Lung><Data><Death><Death Rate><Development><Diabetes Mellitus><Diet><Disease><Disease Outbreaks><Disorder><Dysfunction><Etiology><Expression Signature><Fats><Fatty acid glycerol esters><Functional disorder><Future><Gene Expression Profile><General Population><General Public><Genes><Glycolysis><Goals><Golden Hamsters><Golden Syrian Hamsters><Grippe><H1N1><H1N1 Virus><Hamsters><Hamsters Mammals><Homologous Chemotactic Cytokines><Hospital Admission><Hospital Mortality><Hospitalization><Human><Immune infiltrates><Immune response><Immunological response><Immunomodulation><Impairment><In Vitro><In-house Mortalities><Incidence><Individual><Infection><Infection prevention><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Inflammatory Response><Influenza><Influenza A Virus, H1N1 Subtype><Inhospital Mortality><Innate Immune Response><Intercrines><Ketosis-Resistant Diabetes Mellitus><Lung><Lung Inflammation><Lung Respiratory System><Lung damage><Lung infections><Macrophage><Maturity-Onset Diabetes Mellitus><Mediating><Mesocricetus auratus><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Pathway><Micro RNA><MicroRNAs><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Mφ><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Outbreaks><Outcome><Pathogenesis><Pathogenicity><Patients><Pattern><Phenotype><Physiopathology><Play><Pneumonia><Pneumonitis><Prevent infection><Production><Proteomics><Pulmonary Inflammation><Pulmonary Macrophages><Reporting><Repression><Resistance><Resolution><Risk><Rodent><Rodentia><Rodents Mammals><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 disease severity><SARS-CoV-2 infection><SARS-CoV-2 severity><SARS-CoV2><SARS-CoV2 infection><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Seasons><Severe Acute Respiratory Coronavirus><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Signal Repression><Signal Transduction Pathway><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Stiff lung><Structure><Syrian Hamsters><System><T2 DM><T2D><T2DM><Testing><Therapeutic><Therapeutic Agents><Therapeutic Intervention><Thesaurismosis><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Veterans><Viral><Viral Diseases><Viral Pathogenesis><Viral Respiratory Tract Infection><Virus><Virus Diseases><Wuhan coronavirus><adult onset diabetes><candidate identification><causation><cell growth regulation><chemoattractant cytokine><chemokine><comparative><coronavirus disease 2019><coronavirus disease 2019 disease severity><coronavirus disease 2019 infection><coronavirus disease 2019 severity><coronavirus disease 2019 virus><coronavirus disease severity><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><cytokine><design><designing><developmental><diabetes><diabetic><diabetic patient><diets><disease causation><effective therapy><effective treatment><emergent virus><emerging virus><experiment><experimental research><experimental study><experiments><flu serotype><flu strain><flu subtype><flu viral strain><flu virus strain><gene expression pattern><gene expression signature><hCoV19><high risk><host response><immune cell infiltrate><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><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><influenza serotype><influenza strain><influenza subtype><influenza viral strain><influenza virus strain><innovate><innovation><innovative><intervention therapy><ketosis resistant diabetes><lung function><lung injury><maturity onset diabetes><metabolism disorder><metabolism measurement><metabolomics><metabonomics><miRNA><miRNAs><model of animal><mortality><mortality rate><mortality ratio><multiomics><multiple omics><nCoV2><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><non-diabetic><nondiabetic><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><pandemic><pandemic disease><panomics><pathophysiology><permissiveness><prevent><preventing><prototype><pulmonary><pulmonary damage><pulmonary function><pulmonary infections><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><resistant><resolutions><respiratory><respiratory virus><response><scRNA-seq><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 severity><severe acute respiratory syndrome-CoV><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><sugar><transcriptional profile><transcriptional signature><transcriptomics><type 2 DM><type II DM><type two diabetes><viral emergence><viral infection><viral respiratory infection><virology><virus infection><virus pathogenesis><virus-induced disease><western diet><western-style diet><western-type diet><wet lung>