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Principal Investigator: Philip Murphy
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $11,205
Funding agency: National Institute of Allergy and Infectious Diseases
We have written an Animal Study Proposal that has been approved by the NIAID Animal Care and Use Committee. We have not yet begun research because the BSL3 and ABSL3 facilities were not open until summer 2020. We are awaiting approval of our proposal by the BSL3 review committee. In the 1st Year, WT and huACE2 transgenic mice on a C57BL/6 background will be infected with clinical isolates of SARS-CoV and SARS-CoV-2. In the 2nd Year a strain of SARS-CoV-2 that has been adapted to mouse tissue culture propagation (mSARS-CoV-2) will also be compared with the original clinical isolate of SARS-CoV-2 to determine whether it has greater affinity for mouse ACE2 and greater virulence in C57BL/6 WT mice expressing mouse ACE2. For each type of experiment four virus doses will be tested to determine if models for asymptomatic, mild virulence or higher virulence can be developed for each virus. Both females and males will be tested and are expected to have differences in clinical progression of coronaviral disease and histopathology, based on other infectious disease models in mice, and differences between the sexes observed in humans infected with SARS-CoV and SARS-CoV-2. As a result, they will be treated as separate cohorts but are combined in the numbers in the table below. In this and all subsequent experiments, clinical disease progression will be assessed by virus recovery from throat swabs, blood and stool; serum antibody titers, hemograms, blood chemistries and serum cytokines before and at multiple intervals after infection; as well as physical appearance, weight loss, and progression to moribundity and survival for a month after infection. Animals will be euthanized by CO2 and cervical dislocation at the latest one-month post-infection. In our experience, to observe significant differences in survival we will need 20 mice/cohort in each experiment and repeat the experiment 3 times due to the variance in survival between experiments. These numbers should be sufficient to observe significant differences in the other clinical data as well. Fewer non-infected mice will be needed since there is expected to be less variance among these controls. Animals to be managed as Column E are highlighted in yellow in the tables below for this and subsequent experiments.
Terms: <2019 novel coronavirus><2019-nCoV><Affinity><Animal Care and Use Committees><Animals><Antibodies><Antibody titer measurement><Appearance><Blood><Blood Chemical Analyses><Blood Chemical Analysis><Blood Reticuloendothelial System><Blood Serum><Body Weight decreased><CO2><COVID-19><COVID19><Carbon Dioxide><Carbonic Anhydride><Cervical><Clinical><Clinical Data><Differences between sexes><Differs between sexes><Disease><Disease Progression><Dislocations><Disorder><Dose><Drugs><Feces><Female><Genes><Histopathology><Human><Immune response><Immunological response><Immunomodulation><Individual><Infection><Lung><Lung Respiratory System><Medication><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><NIAID><National Institute of Allergy and Infectious Disease><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharyngeal structure><Pharynx><Play><Recovery><Research><Review Committee><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><Serum><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe acute respiratory syndrome coronavirus 2><Sex Differences><Sexual differences><Site><Swab><Techniques><Testing><Throat><Time><Transgenic Mice><Viral Pathogenesis><Virulence><Virus><Weight Loss><Weight Reduction><Wuhan coronavirus><antibody titering><base><blood chemistry><body weight loss><cohort><corona virus disease 2019><coronavirus disease 2019><cytokine><drug development><drug/agent><experience><experiment><experimental research><experimental study><host response><immune modulation><immune regulation><immune regulator><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><infectious disease model><insight><male><mouse model><murine model><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pulmonary><severe acute respiratory syndrome-CoV><sex-dependent differences><sex-related differences><sex-specific differences><small molecule><social role><stool><tissue culture><virus pathogenesis><wt-loss>