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Principal Investigator: Jean-Laurent Casanova
Organization: ROCKEFELLER UNIVERSITY
Fiscal Year: 2022
Award: $74,534
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
In December 2019, a novel coronavirus (SARS-CoV-2) emerged in the city of Wuhan, China, and quickly spread
worldwide, with an increasing number of cases and deaths. In populations naive to this new pathogen, there has
been immense inter-individual clinical variability among infected individuals, ranging from asymptomatic infection
to lethal coronavirus infectious disease-19 (COVID-19), which is typically due to pneumonitis and rarely to
encephalitis. The infection to severe/life-threatening ratio is estimated to be < 1/1,000 in people <20 years,
around 5/1,000 in people 20-50 years, >1/100 over 50 years, and > 1/10 over 80 years. Underlying medical
conditions also greatly increase the risk of severe COVID-19. On the other hand, rare cases of apparent
resistance to the infection itself have also been identified (viral PCR-negative and seronegative individuals
despite repeated and confirmed exposure). In this context, we hypothesize that monogenic inborn errors of
immunity (IEI) may underlie life-threatening COVID-19 infections in previously healthy, young individuals (<50
years), whereas monogenic inborn variations of resistance (IVR) may protect other individuals from SARS-CoV-
2 infection. Both hypotheses are based on 25 years of studies of a wide range of other viral infections, for which
IEI (e.g. influenza virus pneumonitis) and IVR (e.g. resistance to human immunodeficiency virus) have been
identified. We will recruit both IEI and IVR cohorts not only in the USA but also, importantly, at the international
level; search for candidate disease-causing variants using a cutting-edge strategy developed in our laboratory
to analyze whole-exome sequencing (WES) data; and perform in-depth functional studies to characterize the
products of candidate genotypes biochemically, and to analyze the corresponding patients’ cells immunologically.
Our program aims to discover the human genetic and immunological basis of both severe “idiopathic” COVID-
19 and natural resistance to SARS-CoV-2. Our preliminary results are exciting. In less than 2 months, we and
Helen Su (NIAID) have organized the global and growing “COVID Human Genetic Effort” (CHGE), with over 400
collaborators and 40 sequencing hubs in 50 countries (www.covidhge.com). In the last month, our own hub
sequenced over 100 patients in the IEI cohort and enrolled 2 individuals in the IVR cohort. We have already
selected 5 promising candidate genes (IKFZ1, POLR3C,TLR7, IRF7, IL22), which are all involved in anti-viral
interferon immunity. Our program focuses on a timely problem (severe COVID in previously healthy young
patients and individuals naturally resistant to infection), tests a bold but plausible hypothesis (monogenic basis
for both groups of outliers), and uses cutting-edge genetic and mechanistic studies (including the study of
leukocyte subsets and induced pluripotent stem cells (iPSC)-derived pulmonary epithelial cells). Our project will
permit genetic diagnosis and counseling, while facilitating the development of novel preventive and therapeutic
strategies including anti-viral drugs (e.g. aimed at restoring a deficient immunity or blocking viral entry) and
vaccines (e.g. aimed at boosting certain immunological pathways) in both genetic and non-genetic cases.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AIDS Virus><API3><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adolescent><Adolescent Youth><Antiviral Agents><Antiviral Drugs><Antivirals><Attenuated><BIRC4><BIRC4 gene><Biochemical><Blood leukocyte><Body Tissues><Brain Inflammation><Brain Stem><Brainstem><Burkitt Herpesvirus><Burkitt Lymphoma Virus><C-C CKR-5><C-C CKR-5 Gene><C-C Chemokine Receptor Type 5><C-C Chemokine Receptor Type 5 Gene><CC Chemokine Receptor 5><CC-CKR-5><CC-CKR-5 Gene><CC-CKR5><CCCKR5><CCCKR5 Gene><CCR-5><CCR-5 Gene><CCR5><CCR5 Protein><CCR5 Receptors><CCR5 gene><CD195 Antigen><CD195 Antigen Gene><CD40 Receptor-Associated Factor 1><CD40bp Protein><CHEMR13><CHEMR13 Gene><CKR-5><CKR-5 Gene><CKR5><CKR5 Gene><CKR5 Receptors><CMKBR5><CMKBR5 Gene><CMV><COVID><COVID-19><COVID-19 exposure><COVID-19 infection><COVID-19 predisposition><COVID-19 susceptibility><COVID-19 virus><COVID-19 vulnerability><COVID19><COVID19 infection><COVID19 virus><CRAF1 Protein><CV-19><CV19><Cancers><Candidate Disease Gene><Candidate Gene><Causality><Cell Body><Cells><Cessation of life><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Chickenpox Virus><China><Cities><Clinical><CoV disease><CoV emergence><CoV-2><CoV2><Comment><Commentary><Communicable Diseases><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Country><Cytomegalovirus><Data><Death><Development><Disease><Disease Outbreaks><Disorder><E-B Virus><EB virus><EBV><Editorial Comment><Elderly><Encephalitis><Enrollment><Epithelial Cells><Epstein Barr Virus><Etiology><FLJ11330><Genetic><Genetic Counseling><Genetic Heterogeneity><Genotype><Germinoblastic Sarcoma><Germinoblastoma><HCMV><HHV-3><HHV-4><HHV3><HHV4><HIV><HIV-1 Fusion Co-Receptor><HIV-1 Fusion Co-Receptor Gene><HPV><HSV-1><HSV1><Hemophagocytosis><Hepatitis><Hepatitis A Virus><Hereditary Disease><Herpes Simplex Virus 1><Herpes Simplex Virus Type 1><Herpes zoster Virus><Herpesvirus 1><Herpesvirus Type 3><Herpesvirus varicellae><Histiocytosis haematophagic><Human><Human Genetics><Human Herpesvirus 4><Human Immunodeficiency Viruses><Human Papilloma Virus><Human Papillomavirus><IFN><IFN-regulatory factor 3><IFNAR><IFNAR1><IFNAR1 gene><IFNAR2><IFNAR2 gene><IFNARB><INOS><IRF-3 protein><IRF3><IRF3 gene><ISFG-3><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Inborn Genetic Diseases><Individual><Inducible Nitric Oxide Synthase><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Infectious Human Wart Virus><Infectious Mononucleosis Virus><Influenza Virus><Inherited disorder><Interferon Regulatory Factor 3><Interferons><International><Knowledge><LAP-1 Protein><LAV-HTLV-III><Laboratories><Lesion><Leukocytes><Leukocytes Reticuloendothelial System><Life><Lung><Lung Inflammation><Lung Respiratory 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medication><antiviral therapeutic><base><block viral entry><causation><cohort><corona virus disease><corona virus disease 2019><corona virus emergence><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 exposure><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><cytomegalovirus group><developmental><disease causation><elders><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><emerging pathogen><enroll><exome sequencing><exome-seq><exposure to COVID-19><exposure to SARS-CoV-2><exposure to SARS-CoV2><exposure to Severe acute respiratory syndrome coronavirus 2><exposure to coronavirus disease 2019><genetic diagnosis><genetic disorder diagnosis><geriatric><hCoV19><hereditary disorder><heritable disorder><herpes simplex i><high 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