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Principal Investigator: Paul Kievit
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2024
Award: $951,400
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
The COVID-19 global pandemic caused by the novel SARS-CoV-2 coronavirus continues to result in
significant morbidity and mortality worldwide. Although effective vaccines and therapeutics have been
introduced, COVID-19 will continue to persist as a public health issue as a result of vaccine
resistance/hesitancy and risk of reinfection, the emergence of variants of concern that may evade current
vaccines, and the potential existence of latent viral reservoirs. The adverse outcomes associated with COVID-
19 are increased by a number of pre-existing conditions, notably diabetes, cardiovascular disease, and
hypertension. These conditions share obesity and insulin resistance (IR) as a common underlying feature,
which has raised the question of whether obesity per se is an independent risk factor for more severe COVID-
19 outcomes in the absence of clinically diagnosed diabetes, cardiovascular disease, or hypertension. This
concept is supported by previously described effects of obesity on respiratory disease and the immune
response. Evidence is also accumulating for altered glucose and lipid metabolism and new-onset diabetes in
COVID-19 patients that can persist after recovery from acute infection, and that constitutes an important
component of post-acute sequelae of COVID-19 (PASC). These data suggest that, while obesity and metabolic
disease affect the acute COVID-19, that there are a reciprocal acute and post-acute effects of COVID-19 on
metabolic control. We hypothesize that: (1) obesity/IR in the absence of other conditions such as frank
diabetes, CVD, or hypertension will increase the severity of SARS-CoV-2 infection and acute disease
pathology; and (2) that SARS-CoV-2 infection will exacerbate pre-existing preclinical metabolic disease as
reflected in progression to more advanced, clinically evident disease. We propose to address these
hypotheses through pursuit of the following specific aims.
Specific Aim 1. Determine the effect of pre-existing obesity/IR on the acute response to SARS-CoV-2 infection.
Specific Aim 2. Determine the effect of SARS-CoV-2 infection on the post-acute progression of metabolic
disease.
We will employ a nonhuman primate preclinical model of lean, metabolically healthy and obese, insulin-
resistant adult male rhesus macaques infected with SARS-CoV-2 over a 2-week (acute phase) or 6-month
(post-acute) course of disease, during which time comprehensive longitudinal assessments of viral load, lung
pathology, peripheral and adipose immune cell responses, and glucose and lipid metabolism will be performed.
At necropsy following the acute and post-acute studies, islet function will be assessed and multiple tissue
samples collected for determination of viral distribution and persistence in potential latent reservoirs. The
proposed studies represent a unique opportunity to elucidate the mechanisms underlying the reciprocal
relationship between COVID-19 and metabolic disease in an experimentally tractable preclinical model.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><21+ years old><Acceleration><Acute><Acute Disease><Address><Adipocytes><Adipose Cell><Adipose tissue><Adult><Adult Human><Affect><Alveolar><Anatomic Sites><Anatomic structures><Anatomy><Animals><Antigens><Appearance><Autopsy><B.1.617.2><Biological Markers><Blood><Blood Reticuloendothelial System><Body Tissues><C-Peptide><COVID crisis><COVID disease severity><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID severity><COVID survivors><COVID-19><COVID-19 affected><COVID-19 consequence><COVID-19 crisis><COVID-19 disease severity><COVID-19 effect><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 impact><COVID-19 impacted><COVID-19 infected patient><COVID-19 infection><COVID-19 infection survivors><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related risk><COVID-19 risk><COVID-19 risk factor><COVID-19 severity><COVID-19 survivors><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID-19 years><COVID19 disease severity><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 severity><COVID19 virus><CV-19><Cardiac Diseases><Cardiac Disorders><Cardiovascular Diseases><Cell Body><Cells><Chronic><Clinical><CoV-2><CoV2><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><D-Glucose><Data><Delta variant><Dextrose><Diabetes Mellitus><Disease><Disorder><Endocrine><Endothelial Cells><Exhibits><Fat Cells><Fatty Tissue><Foundations><Glucose><Glycohemoglobin A><Glycosylated hemoglobin A><Hb A1><Hb A1a+b><Hb A1c><HbA1><HbA1c><Heart Diseases><Hemoglobin A(1)><Hospital Admission><Hospitalization><Human><Humulin R><Hyperinsulinemia><Hyperinsulinism><Hypertension><Immune><Immune response><Immunes><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunological response><Impairment><Individual><Infection><Inflammation><Insulin><Insulin Resistance><Intermediary Metabolism><Lavage><Leanness><Light><Link><Lipids><Lipocytes><Lung><Lung Respiratory System><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Macrophage><Mature Lipocyte><Mature fat cell><Metabolic><Metabolic Control><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Modeling><Modern Man><Monitor><Morbidity><Morbidity - disease rate><Morphology><Mφ><Nature><Newly Diagnosed><Novolin R><Nucleic Acids><Obesity><Oral><Outcome><PASC><Pancreas><Pancreatic><Pathology><Patients><Peripheral><Phase><Photoradiation><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Pre-Clinical Model><Preclinical Models><Predisposition><Public Health><Pulmonary Pathology><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><Recovery><Regular Insulin><Reporting><Resistance><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Respiratory physiology><Rhesus Macaque><Rhesus Monkey><Risk><Risk Factors><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 B.1.617.2><SARS-CoV-2 delta><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 survivors><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 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patient><coronavirus disease positive patient><coronavirus disease severity><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 impact><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><corpulence><cytokine><develop therapy><diabetes><diet-associated obesity><diet-induced obesity><diet-related obesity><disease severity><endothelial dysfunction><fasting glucose><fat metabolism><glucose control><glucose homeostasis><glucose metabolism><glucose regulation><glucose tolerance><glycemic control><hCoV19><heart disorder><hemoglobin A1c><high blood pressure><host response><human tissue><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><immune system response><immunogen><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><insulin resistant><insulin secretion><insulin tolerance><intervention development><islet><lavage therapy><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lipid metabolism><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><lung pathology><male><metabolic phenotype><metabolism disorder><metabotype><mortality><nCoV2><nasal swab><necropsy><non-human primate><nonhuman primate><novel><obese individuals><obese people><obese person><obese population><obese subjects><outcome following vaccination><outcome following vaccine><pandemic><pandemic disease><patient 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disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><subcutaneous><subdermal><survive COVID-19><survive SARS-CoV-2><therapy development><treatment development><vaccination outcome><vaccination result><vaccine outcome><vaccine result><variants of concern><viraemia><viral sepsis><virus antigen><virusemia><western diet><western-style diet><western-type diet><white adipose tissue><yellow adipose tissue>