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Principal Investigator: Jyoti K Jaiswal
Organization: CHILDREN'S RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $569,440
Funding agency: National Heart Lung and Blood Institute
The leading cause of hospitalization and death in children with trisomy 21 (TS21), also known as Down
syndrome (DS), is lower respiratory tract infection (LRTI). Children with DS have nine times higher risk of
hospitalization and mortality due to LRTIs caused by respiratory syncytial virus (RSV). Understanding the
mechanisms driving the high susceptibility to severe viral LRTI in DS is needed to develop novel therapeutic
strategies to treat this condition. As chromosome 21(HSA21) encodes four of the six known Interferon (IFN)
receptors, TS21 results in triplication of these receptor genes leading to IFN hyperactivation in DS. With the
central role of IFNs on antiviral defense, it remains puzzling how IFN hyperactivation contributes to severe viral
LRTIs in DS. Through preliminary studies we show that, compared to euploid controls, airway epithelial cells
(AECs) from children with DS exhibit IFN-induced dysregulation of NRF2, a transcription factor essential for the
antioxidant response required to limit RSV replication. The AECs of children with DS also show dysregulated
expression of BACH1 and its inhibitor miR-155, both of which are located on HSA21, and regulate NRF2-
dependent AEC antioxidant responses during viral infection. Thus, our results identify a novel mechanism of
impaired airway antiviral responses in TS21, and provide an unexpected molecular nexus between two widely
recognized cellular pathologies in DS - dysregulated IFN activation (interferonopathy) and oxidative imbalance.
Our central hypothesis is that hyperactivation of IFN in the airway epithelium of children with DS
dysregulates BACH1 signaling, leading to reduced antiviral and NRF2-driven antioxidant responses
and greater severity of viral respiratory infection. Our study will address the historical exclusion of DS
children from research related to airway antiviral immunity, and thus will have a transformative potential to
improve their health and survival. To elucidate the mechanisms of pathogenesis of severe viral respiratory
infections in DS and develop innovative precision medicine approaches for this vulnerable population, we
propose three aims: AIM 1: Define the role of IFN-induced BACH1 dysregulation during viral respiratory
infection in the airway epithelium of children with DS. AIM 2: Investigate how interferonopathy and altered
miR-155 expression dysregulates antioxidative and antiviral responses in the airway epithelium of children with
DS. AIM 3: Establish the association of dysregulated antioxidative and antiviral responses in DS with greater
disease severity during respiratory viral infection. The result of this human-based transformative study will
define a previously unrecognized targetable mechanism causing dysregulated anti-oxidative and antiviral
responses in TS21. This ground-breaking knowledge will greatly move forward our understanding of the
pathobiology of severe viral LRTI in DS and will provide the essential molecular foundation for the development
of new diagnostic tools and highly innovative therapies.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><Adult><Adult Human><Agonist><Airway infections><Anti-viral Response><Antioxidants><Automobile Driving><BACH1><BACH1 gene><Basal Transcription Factor><Basal transcription factor genes><Blood Sample><Blood specimen><COVID-19 virus><COVID19 virus><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><ChIP Sequencing><ChIP-seq><ChIPseq><Child><Child Youth><Children (0-21)><Chromosome 21><Clinical><CoV-2><CoV2><Cytometry><Death><Development><Down's Syndrome><Dysfunction><Epithelial Cells><Equilibrium><Exclusion><Exhibits><Exposure to><Foundations><Functional disorder><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><Health><Hospital Admission><Hospitalization><Human><IFN><IFN activation><Immune><Immune response><Immunes><Immunological response><Innovative Therapy><Interferon Activation><Interferon Receptor><Interferons><Intracellular Communication and Signaling><Knowledge><Langdon Down syndrome><Lower Respiratory Tract Infection><Lower respiratory infection><Mediating><Modern Man><Molecular><Mongolism><Nasal><Nasal Passages Nose><Nose><Pathogenesis><Physiopathology><Predisposition><RNA Expression><RSV infection><Receptor Gene><Recovery><Research><Respiratory Epithelium><Respiratory Infections><Respiratory Syncytial Virus Infections><Respiratory System, Nose, Nasal Passages><Respiratory Tract Infections><Respiratory syncytial virus><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-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><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-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 related corona virus 2><Severities><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Structure of respiratory epithelium><Susceptibility><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Trisomy 21><Up-Regulation><Upregulation><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus><Virus Diseases><Virus Replication><Vulnerable Populations><Wuhan coronavirus><adulthood><airway epithelium><airway injury><anti-viral immunity><antiviral immunity><balance><balance function><biological signal transduction><cellular pathology><chromatin immunoprecipitation-sequencing><chromosome 21 trisomy syndrome><congenital acromicria syndrome><coronavirus disease 2019 virus><coronavirus disease-19 virus><developmental><diagnostic tool><disease severity><driving><hCoV19><high risk><host response><immune system response><immunoresponse><impaired airway><improved><in vivo><inhibitor><injured airway><innovate><innovation><innovative><kids><morbus Down><mortality><nCoV2><new approaches><new diagnostics><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><next generation diagnostics><novel><novel approaches><novel diagnostics><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><precision medicine><precision-based medicine><prevent><preventing><pseudohypertrophic progressive muscular dystrophy><public health relevance><respiratory injury><respiratory tract epithelium><respiratory tract injury><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><transcription factor><trisomy 21 syndrome><viral infection><viral multiplication><viral replication><viral respiratory infection><virus infection><virus multiplication><virus-induced disease><vulnerable group><vulnerable individual><vulnerable people><youngster>