Document text
Principal Investigator: Jyoti K Jaiswal
Organization: CHILDREN'S RESEARCH INSTITUTE
Fiscal Year: 2020
Award: $489,740
Funding agency: National Heart Lung and Blood Institute
ABSTRACT
Down syndrome (DS), also known as trisomy 21, is the most common chromosomal abnormality among live-
born infants. DS is associated with a disproportionate high risk for severe viral respiratory infections, a top
cause of mortality in this vulnerable population. Nonetheless, the risk of DS patients to develop severe SARS-
CoV-2 infections during the COVID-19 pandemic has been remarkably understudied. A major concern in DS
individuals the risk to develop hyper-inflammatory responses manifested as cytokine storm and/or multisystem
inflammatory syndrome in children. Indeed, people with DS exhibit hyper-activation of interferon (IFN) signaling
because they have three copies of the chromosome 21, which encodes four of the six IFN receptors.
Importantly, our team and others recently identified that IFNs are strong inducers of the angiotensin-converting
enzyme 2 (ACE2), the cell entry receptor of SARS-CoV-2 in the human airway epithelium. The novel finding
that SARS-CoV-2 may tap into the host IFN-driven airway epithelial antiviral response to enhance its infectivity
represents a paradigm shift for the pathobiology of COVID19, particularly in individuals with DS. The overall
goal of this application is to investigate, for the first time, the airway epithelial IFN-driven antiviral and pro-
inflammatory responses in young children with DS. Our NIH-funded laboratory (R01HL141237) has the
expertise to study the immunobiology of the airway epithelial cell (AEC) of young children, the age group with
the highest risk for severe viral respiratory infections. Our central hypothesis is that the airway epithelium
of DS children exhibits a dysregulated antiviral molecular program leading to enhanced production of
pro-inflammatory cytokines and IFNs (Aim 1); and heightened responsiveness to IFNs leading to
overexpression of ACE2 and increased susceptibility to SARS-CoV-2 infection (Aim 2). Defining the key
innate cytokines/chemokines and the precise molecular pathways dysregulated in the AEC of DS individuals
promises a unique opportunity to discover novel targets to treat severe viral respiratory infections, including
SARS-CoV-2. This new knowledge may have long-lasting impact for people with DS by identifying potentially
novel approaches to prevent severe respiratory infections caused by SARS-CoV-2 and other viruses (e.g.
RSV) in children and adults with DS.
Terms: <0-11 years old><2019 novel coronavirus><2019-nCoV><21+ years old><Aberrant Chromosome><Active Follow-up><Address><Adult><Adult Human><Angiotensin AT2 Receptor><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin Receptor 2><Anti-Viral Response><Antiviral Agents><Antiviral Drugs><Antiviral Response><Antivirals><Applications Grants><Area><Assay><Binding Sites><Bioassay><Biologic Assays><Biological Assay><CD143 Antigens><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Carboxycathepsin><Caring><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemotactic Cytokines><Child><Child Youth><Children (0-21)><Chromosomal Aberrations><Chromosomal Abnormalities><Chromosomal Alterations><Chromosome 21><Chromosome Aberrations><Chromosome Alterations><Chromosome Anomalies><Chromosome abnormality><Clinical Trials><Combining Site><Confocal Microscopy><Cytogenetic Aberrations><Cytogenetic Abnormalities><Dipeptidyl Peptidase A><Down Syndrome><Down's Syndrome><Downs Syndrome><Epithelial Cells><Exhibits><Exposure to><Foundations><Funding><Future><Genes><Genetic><Goals><Grant Proposals><Homologous Chemotactic Cytokines><Human><Human Figure><Human body><IFN><Immunoassay><Immunobiology><Immunoblotting><Immunophysiology><Individual><Infant><Infection><Inflammatory><Inflammatory Response><Intercrines><Interferon Activation><Interferon Receptor><Interferons><Intracellular Communication and Signaling><Investigation><Kininase A><Kininase II><Knowledge><Laboratories><Langdon Down syndrome><Modern Man><Molecular><Molecular Target><Mongolism><NIH><Nasal><Nasal Passages Nose><National Institutes of Health><Nose><Pathway interactions><Patients><Peptidyl-Dipeptidase A><Poly I-C><Polyinosinic-Polycytidylic Acid><Population><Predisposition><Production><RNA Seq><RNA sequencing><RNAseq><Reactive Site><Receptor Gene><Receptor Protein><Receptor, Angiotensin, Type 2><Research><Respiratory Infections><Respiratory System, Nose, Nasal Passages><Respiratory Tract Infections><Risk><Role><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><SIS cytokines><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe acute respiratory syndrome coronavirus 2><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Susceptibility><Syndrome><Testing><Time><Trisomy 21><Type 2 Angiotensin II Receptor><United States National Institutes of Health><Up-Regulation><Upregulation><Viral><Viral Respiratory Tract Infection><Virus><Vulnerable Populations><Work><Wuhan coronavirus><active followup><adulthood><age group><airway epithelium><anti-viral agents><anti-viral drugs><anti-virals><biological signal transduction><chemoattractant cytokine><chemokine><children><childrens'><chromosomal defect><chromosome 21 trisomy syndrome><chromosome defect><clinical relevance><clinically relevant><congenital acromicria syndrome><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><cytokine><cytokine release syndrome><cytokine storm><follow up><follow-up><followed up><followup><high risk><interferon therapy><morbus Down><mortality><new approaches><novel><novel approaches><novel strategies><novel strategy><overexpress><overexpression><pathway><poly IC><prevent><preventing><programs><pseudohypertrophic progressive muscular dystrophy><public health relevance><receptor><respiratory infection virus><respiratory virus><response><severe acute respiratory syndrome-CoV><social role><transcriptome sequencing><transcriptomics><trisomy 21 syndrome><viral respiratory infection><vulnerable group><youngster>