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Principal Investigator: SUNDARAM RAMAKRISHNAN
Organization: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
Fiscal Year: 2021
Award: $153,500
Funding agency: National Institute on Drug Abuse
Project Summary
Infection with Covid-19 has reached pandemic status with more than 125 million confirmed cases and 2.75
million deaths making it one of the most deadliest pandemics in history. It is associated with severe acute
respiratory syndrome symptoms with high fatality rates. SARS-CoV-2 infection is initiated when its S-protein
binds to the angiotensin-converting enzyme 2 (ACE2) receptor through which it gains entry into the host's cells
(Kuba et al., 2005; Walls et al., 2020). ACE2 is highly expressed in the in the lungs and to a lesser degree in
other organs, such as the heart, kidneys, and intestines (Bavishi et al., 2020), which explains the increased
prevalence of lung infection. An analysis of electronic health record data from more than 73 million patients
showed that people with SUDs are at higher risk of contracting and suffering worse consequences from COVID-
19 particularly among African Americans. Those with an opioid use disorder (OUD) were 2.4 times more likely
to have COVID-19 than those with cocaine use disorder (1.6 times), alcohol use disorder (1.4 times), and
tobacco use disorder (smoking or vaping; 1.3 times). Our recent preliminary data show that chronic opioid
treatment in a mouse model of opioid substance abuse resulted in significant increase in the expression ACE2
expression in the lungs and brain of these animals. This data suggests that long term exposure to opioids by
increasing ACE2 expression in the lung will increase the susceptibility to COVID 19 infection and its expression
in the brain suggests high likely hood of neuro-invasiveness. In this supplement we will test the hypothesis that
substance use disorders with opioids will increase the risk for COVID 19 infection in the lung and will be
associated with neuropathological consequence as a consequence of increased ACE2 expression in brain cells.
In Aim 1: We will investigate the expression of ACE2 in small intestine, lung and brain cells in both male and
female mice that are chronically treated with morphine. We will further investigate if substance abuse in context
of HIV further exacerbates infection and disease progression. In Aim 2; we will investigate using a humanized
mouse model where the murine ACE2 receptor is knocked in, the infectivity of the SARS-CoV2 Spike Protein-
Pseudotyped GFP using both in vitro and in vivo target cells. In Aim 3 we will investigate the role of the gut
microbiome in modulating ACE2 expression levels in the small intestine, lung and brain.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><African American><Afro American><Afroamerican><Animals><Attenuated><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Binding><Binding Proteins><Binding Sites><Biologic Models><Biological><Biological Models><Black Populations><Blood Circulation><Blood Serum><Bloodstream><Body Tissues><Brain><Brain Nervous System><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 infection><COVID-19 mortality><COVID-19 patient><COVID-19 positive patient><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19><COVID19 S protein><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 patient><COVID19 positive patient><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CV-19><CV19><Cell Body><Cells><Cessation of life><Chronic><Circulation><Cleaved cell><Clinical Data><CoV-2><CoV2><Combining Site><Contracting Opportunities><Contracts><Data><Death><Disease><Disease Progression><Disorder><Elastases><Electronic Health Record><Encephalon><Environment><Enzyme Gene><Enzymes><Epitheliasin Gene><Esteroproteases><Exposure to><Fatality rate><Female><GI microbiome><Glycoproteins><Goals><HIV><HIV Infections><HPGF><HTLV-III Infections><HTLV-III-LAV Infections><Heart><Hepatocyte-Stimulating Factor><History><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune Cell Activation><In Vitro><Infection><Inflammasome><Infumorph><Interleukin-6><Intestinal><Intestines><Kadian><Kidney><Kidney Urinary System><Knock-in><LAV-HTLV-III><Ligand Binding Protein><Ligand Binding Protein Gene><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung infections><Lymphadenopathy-Associated Virus><MGI-2><MS Contin><MSir><Membrane><Mesencephalon><Mice><Mice Mammals><Mid-brain><Midbrain><Midbrain structure><Model System><Modern Man><Molecular Interaction><Morphia><Morphine><Murine><Mus><Myeloid Differentiation-Inducing Protein><NIDA><National Institute of Drug Abuse><National Institute on Drug Abuse><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological Manifestations><Neurological Signs and Symptoms><Opiate user><Opiates><Opioid><Opioid drug user><Oramorph><Oramorph SR><Organ><PRSS10><PWUO><Patients><Peptidases><Peptide Hydrolases><Peptides><Plasmacytoma Growth Factor><Play><Predisposition><Prevalence><Protease Gene><Proteases><Protein Binding><Proteinases><Proteins><Proteolytic Enzymes><Publishing><Reactive Site><Receptor Protein><Recording of previous events><Reporting><Respiratory Failure><Risk><Role><Route><Roxanol><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><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><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><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 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Small Intestines><Smoking><Statex SR><Structure of parenchyma of lung><Substance Use Disorder><Substance abuse problem><Susceptibility><Symptoms><TMPRSS2><TMPRSS2 gene><Testing><Time><Tissues><Tobacco Use Disorder><Transgenic Organisms><Viral><Virus><Virus-HIV><Wuhan coronavirus><abuse of substances><alcohol use disorder><angiotensin converting enzyme 2><angiotensin converting enzyme II><black American><bound protein><bowel><brain cell><brain tissue><cleaved><cocaine use><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus patient><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><digestive tract microbiome><dysbacteriosis><dysbiosis><dysbiotic><electronic health care record><electronic healthcare record><enteric microbiome><ethanol use disorder><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><gastrointestinal microbiome><gut microbiome><gut-associated microbiome><hCoV19><high risk><humanized mice><humanized mouse><immune activation><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><interferon beta 2><intestinal biome><intestinal epithelium><intestinal microbiome><knockin><lung failure><male><membrane structure><microbial><microbial imbalance><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><mouse model><murine model><nCoV2><neural manifestation><neuropathology><opiate abuse><opiate drug abuse><opiate exposed><opiate exposure><opiate use disorder><opioid abuse><opioid drug abuse><opioid exposed><opioid exposure><opioid use disorder><opioid user><overexpress><overexpression><pandemic><pandemic disease><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><people who use opioids><persons who use opioids><pulmonary><pulmonary failure><pulmonary infections><receptor><renal><respiratory><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><small bowel><social role><substance abuse><substance use><substance using><tissue tropism><transgenic><vaping>