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Principal Investigator: Megan Sykes
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2020
Award: $283,116
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary: There is growing evidence that an overexuberant innate and adaptive immune response
may contribute to life-threatening pulmonary pathology in COVID-19 disease. On the other hand, inadequate
viral control may allow severe disease to develop. Human immune system (HIS) mouse models have enormous
and unique potential to model human COVID-19. Unlike other animal models, HIS mice could be used to
understand the role of the innate and adaptive human immune systems in both controlling and driving SARS-
CoV2-mediated disease and hence be used to optimize therapeutic approaches. The goal of our proposal is to
optimize HIS mouse models for these purposes. Specifically, we propose to: 1) Optimize our HIS mouse
models for the study of COVID-19. Existing mouse models are limited by the lack of human ACE2, the SARS-
CoV2 receptor, in the respiratory tract. We will implant iPS cell-derived human lung bud organoids generated
from cord blood HSC donor cells into HLA-A2 Tg NSG mice receiving HLA-A2+ cord blood HSCs. In a second
approach to humanizing mice for COVID-19 mouse studies, we will use CRISPR/Cas9 to replace the murine
ACE2 gene with hACE2, allowing physiologic expression of hACE2 in NSG mice. Human HSC recipients will be
treated with mouse TSLP in an AAV vector to enhance murine thymic and lymph node structure and thereby
improve human T cell development and improve peripheral vaccination responses. An alternative approach to
enhancing thymus function will involve grafting of multiple pieces of thymocyte-depleted neonatal human thymus
tissue in multiple sites to compensate for the lack of growth potential (compared to fetal thymus) of neonatal
thymus tissue. Immune reconstitution, T cell reconstitution and lymphoid structure will be followed and humoral
and cellular responses to live attenuated SARS-CoV2 virus vaccination will be measured; 2) Use optimized HIS
mouse models to determine the kinetics of disease pathogenesis and the role of human immune
components in controlling infection and mediating pathologic host responses. We will first employ HIS
mice constructed with human cord blood HSCs and autologous iPSC-derived lung bud implants and later utilize
the above HLA-A2 hACE2 Tg model. Baseline infection with SARS-CoV2 will be assessed in non-reconstituted
animals and compared to HIS mice. In HIS mice, we will deplete various human immune components (T cells,
B cells or macrophages) to determine their impact on the course of infection and pathology associated with
SARS-CoV2. In hACE2 Tg mice we will investigate the kinetics of infection of various components of the
respiratory tract in combination with analysis of the human immune cell infiltrates in each locale over time. With
these models established, we will be positioned to test therapeutic approaches during different phases
of SARS-CoV2 infection in future studies. Collectively, our models will provide critical information on the role
of human immune components in driving and protecting from COVID-19-associated pathology, allowing
accelerated optimization of immunomodulatory therapies.
Terms: <2019 novel coronavirus><2019-nCoV><AAV vector><Address><Allograft Tolerance><Animal Model><Animal Models and Related Studies><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Antiviral Agents><Antiviral Drugs><Antivirals><Attenuated><Autologous><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><COVID-19><COVID19><CRISPR><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cells><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Code><Coding System><Cord Blood><Development><Disease><Disorder><Embryo><Embryonic><Evaluation><Future><Generalized Growth><Genes><Goals><Growth><Gut Epithelium><HLA Class I Histocompatibility Antigen, A-2 Alpha Chain><HLA-A Class I Antigen 2><HLA-A Histocompatibility Type Antigen 2><HLA-A2><HLA-A2 Antigen><Human><Immune><Immune Modulation Therapy><Immune infiltrates><Immune response><Immune system><Immunes><Immunodeficient Mouse><Immunological response><Immunomodulation><Implant><Infection><Inflammation><Intestinal><Intestines><Kinetics><Laboratories><Life><Locales><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Major Histocompatibility Complex, Class I, A2 Antigen><Measures><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Neonatal><Organoids><Pathogenesis><Pathologic><Pathology><Pathway interactions><Patients><Peripheral><Phase><Physiologic><Physiological><Position><Positioning Attribute><Pre-Clinical Model><Preclinical Models><Pulmonary Body System><Pulmonary Organ System><Pulmonary Pathology><Receptor Protein><Regulatory Element><Respiratory Epithelium><Respiratory System><Respiratory Tracts><Respiratory tract structure><Role><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Series><Severe acute respiratory syndrome coronavirus 2><Site><Structure><Structure of parenchyma of lung><Structure of respiratory epithelium><Study models><T cell infiltration><T cell reconstitution><T cell tumor trafficking><T-Cell Development><T-Cell Ontogeny><T-Cells><T-Lymphocyte><T-Lymphocyte Development><TSLP><TSLP gene><Testing><Therapeutic><Thymic Stromal Lymphopoietin><Thymic Tissue><Thymus><Thymus Gland><Thymus Proper><Thymus Reticuloendothelial System><Time><Tissue Growth><Transgenic Mice><Tumor-infiltrating immune cells><Umbilical Cord Blood><Vaccination><Viral><Virus><Wuhan coronavirus><adaptive immune response><adeno-associated viral vector><adeno-associated virus vector><allergic/immunologic body system><allergic/immunologic organ system><anti-viral agents><anti-viral drugs><anti-virals><antiinflammatory><base><bowel><corona virus disease 2019><coronavirus disease 2019><cytokine><cytokine release syndrome><cytokine storm><developmental><driving><experiment><experimental research><experimental study><fetal><fetal cord blood><gastrointestinal epithelium><host response><human model><human stem cells><iPS><iPSC><iPSCs><immune cell infiltrate><immune infiltration><immune modulating therapies><immune modulation><immune modulatory therapies><immune reconstitution><immune regulation><immune regulator><immune-modulation treatment><immunologic reactivity control><immunomodulation therapy><immunomodulation treatment><immunomodulatory><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><immunoregulation><immunoregulatory><immunoresponse><improved><induced pluripotent stem cell><innovate><innovation><innovative><intratumoral immune cell><intravenous injection><lung pathology><lymph gland><lymph nodes><lymphnodes><lymphoid structures><macrophage><model of animal><model of human><model organism><mouse model><murine model><neonatal human><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><ontogeny><pathway><pulmonary><receptor><response><social role><therapeutic evaluation><therapeutic testing><thymocyte><thymus derived lymphocyte><tumor immune cell><vaccination strategy><vector>