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Principal Investigator: Alexander Viloria Winnett
Organization: CALIFORNIA INSTITUTE OF TECHNOLOGY
Fiscal Year: 2022
Award: $51,752
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Morbidity and mortality in COVID-19 is the result of an exaggerated inflammatory response causing severe tissue
and organ damage. However, the biological mechanism for why some individuals progress from initially stable
to ultimately critical condition has not been fully elucidated. This work proposes that the immune response at the
site of infection during the earliest stage of infection plays a deterministic role on subsequent pathology; namely
that a delayed or suppressed type 1 interferon response in the respiratory mucosa within the first few days of
infection permits rapid viral proliferation with minor symptoms, but eventually leads to the high viral loads and
exaggerated inflammatory response seen later in disease. Further, the proposed project will test whether a
delayed interferon response is the result of previously documented age-related dysfunction. It also seeks to
determine whether direct SARS-CoV-2 mediated disruption of host splicing can also suppress interferon
signaling in the early stage of infection. To do this, the study will leverage a unique set of longitudinal paired
nasal swab and saliva samples from individuals who are initially negative for SARS-CoV-2 infection, but become
infected while being prospectively sampled with high frequency (twice per day) as part of an IRB-approved (#20-
1026) COVID-19 household transmission study that the applicant co-designed and co-leads (since August 2020)
at the California Institute of Technology. The transcriptome present in these samples will be analyzed to measure
gene and isoform expression from which leukocyte recruitment and activation, including through interferon
signaling can be inferred, through the elusive early stage of infection and the full course of the illness.
Longitudinal differential expression and differential splicing paths in patients as young as age 6, and of advanced
age will be assessed to identify whether age-related differences in immune response (in particular, interferon
signaling) lead to more rapid increases in viral load, and subsequent symptom severity. In addition, from an RNA
sequencing library enriched for nascent pre-mRNAs, splicing defects such as intron retention will be measured,
to identify whether virus-mediated disruption of splicing also leads to a suppressed or delayed early interferon
response permissive of rapid viral proliferation. COVID-19 is a public health threat, and in line with the mission
of the NIAID, the results of this study can provide mechanistic insights into the pathophysiology of SARS-CoV-2
infection, to potentially identify novel or more efficient targets for the prevention or treatment of severe disease.
In addition, the proposed project offers an excellent training opportunity for the applicant to gain knowledge and
skills in immunology, virology/coronavirus biology, mechanisms of human RNA splicing, and generation analysis
and interpretation of RNA sequencing data, with mentorship from Dr. Rustem Ismagilov, Dr. Akiko Iwasaki, and
Dr. Mitch Guttman, who are experts in the aforementioned fields.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><Accounting><Acute><Adult><Adult Human><Age><Airway mucosa><Anti-Viral Response><Antiviral Response><Autopsy><Biological><Biology><Blood leukocyte><Body Tissues><COVID-19><COVID-19 infection><COVID-19 negative><COVID-19 virus><COVID19><COVID19 infection><COVID19 negative><COVID19 virus><CV-19><CV19><California><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Characteristics><Child><Child Youth><Children (0-21)><Clinical><CoV-2><CoV2><Collaborations><Coronaviridae><Coronavirus><Data><Data Set><Dataset><Defect><Development><Disease><Disease Progression><Disorder><Dysfunction><Elderly><Enrollment><Frequencies><Functional disorder><Gamma interferon><Gene Transcription><Generations><Genes><Genetic Transcription><Grippe><Household><Human><IFN><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IRB><IRBs><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Interferon><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunes><Immunobiology><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunology><Immunomodulation><Immunophysiology><Individual><Infection><Inflammatory><Inflammatory Response><Influenza><Institutes><Institutional Review Boards><Interferon Gamma><Interferon Suppression><Interferon Type II><Interferon-gamma><Interferons><Intervening Sequences><Intracellular Communication and Signaling><Introns><Isoforms><Kinetics><Knowledge><Laboratories><Lead><Leukocytes><Leukocytes Reticuloendothelial System><Libraries><Marrow leukocyte><Measurement><Measures><Mediating><Mentorship><Messenger RNA><Minor><Mission><Modern Man><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Immune Responses><Mucosal Tissue><Mucous Membrane><NIAID><National Institute of Allergy and Infectious Disease><Non-sense Mediated Decay><Non-structural Protein><Nonsense-Mediated Decay><Nonstructural Protein><Nucleic Acids><Obesity><Ontology><Organ><Pathology><Pathway interactions><Patients><Pb element><Phase><Physiopathology><Play><Pre-mRNA><Prevention><Prophylactic treatment><Prophylaxis><Protein Isoforms><Protein Trafficking><Public Health><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Expression><RNA Seq><RNA Splicing><RNA sequencing><RNA, Messenger, Precursors><RNAseq><Research Grants><Research Project Grants><Research Projects><Research Specimen><Respiratory Mucosa><Risk Factors><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV-2 negative><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Saliva><Sampling><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Severities><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Site><Specimen><Splicing><Symptoms><Technology><Testing><Tissue Sample><Tissues><Transcript><Transcription><Translations><Transmission><Treatment Effectiveness><Viral><Viral Burden><Viral Load><Viral Load result><Viral load measurement><Virus><White Blood Cells><White Cell><Work><Wuhan coronavirus><acute infection><adiposity><adulthood><advanced age><age dependent><age related><ages><biologic><biological signal transduction><cell culture><cell cultures><computational tools><computerized tools><corona virus><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 negative><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><corpulence><depository><design><designing><developmental><differential expression><differentially expressed><disease severity><elders><enroll><geriatric><global gene expression><global transcription profile><hCoV19><heavy metal Pb><heavy metal lead><high risk><host response><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><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><insight><interest><lFN-Gamma><late life><later life><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><mRNA><mRNA Precursor><mRNA seq><mRNA sequencing><mRNA-seq><mRNAseq><mortality><nCoV2><nasal swab><necropsy><novel><older adult><older person><pathophysiology><pathway><postmortem><premRNA><prospective><protein transport><recruit><repository><respiratory><response><saliva sample><salivary sample><senior citizen><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 negative><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><skills><social role><temporal measurement><temporal resolution><therapeutic target><time measurement><training opportunity><transcriptional differences><transcriptome><transcriptome sequencing><transcriptomics><transmission process><virology><virus load><white blood cell><white blood corpuscle><youngster>