Rapid Evaluation and Development of Cellular and Animal Tools to fight SARS-CoV-2

  • Funded by Swiss National Science Foundation (SNSF)
  • Total publications:14 publications

Grant number: 196062

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Key facts

  • Disease

    COVID-19
  • Start & end year

    2020
    2022
  • Known Financial Commitments (USD)

    $325,521.31
  • Funder

    Swiss National Science Foundation (SNSF)
  • Principal Investigator

    Benarafa Charaf
  • Research Location

    Switzerland
  • Lead Research Institution

    Institut für Virologie und Immunologie IVI Sensemattstrasse 293 3147 Mittelhäusern
  • Research Priority Alignment

    N/A
  • Research Category

    Pathogen: natural history, transmission and diagnostics

  • Research Subcategory

    Disease models

  • Special Interest Tags

    N/A

  • Study Type

    Non-Clinical

  • Clinical Trial Details

    N/A

  • Broad Policy Alignment

    Pending

  • Age Group

    Not Applicable

  • Vulnerable Population

    Not applicable

  • Occupations of Interest

    Not applicable

Abstract

At the end of December 2019, an outbreak of an unexplained viral pneumonia emerged in Wuhan, Hubei Province, China. The agent was identified as a new coronavirus that is currently referred to as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and is known as the etiological agent of Coronavirus Disease 2019 (COVID-19). Despite unprecedented public health measure by the Chinese and other governments to contain the SARS-CoV-2 outbreak, there are now over 300'000 confirmed cases reported worldwide and more than 14'000 deaths. Numbers continue to rise exponentially in many parts of the world despite rigorous global public health measures and state-enforced quarantine of whole communities and countries. There are currently no approved interventions such as antiviral drugs, vaccines and immuno-prophylaxis available that can be readily used as a prophylactic or therapeutic treatment to halt the current SARS-CoV-2 pandemic. The development of novel antiviral drugs, immunotherapies and vaccines against SARS-CoV-2 will have to be evaluated in pre-clinical animal models before being administered to humans as prevention or intervention strategies. To fulfill this major gap in the process of testing new therapeutic solutions and to increase knowledge in the pathogenesis of SARS-CoV-2, we propose the following specific aims: Aim 1: we will use an authentic in vitro model of the respiratory epithelium with air-liquid interface airway epithelial cells (AECs) to identify suitable domestic and wild animal models susceptible to SARS-CoV-2Aim 2a: we will revisit and improve the mouse model developed following for the SARS-CoV epidemic in 2002/2003 and investigate human ACE2 expressed under the endogenous mouse Ace2 promoter, as ACE2 is a shared receptor between SARS-CoV-2 and SARS-Cov. Both in vitro and in vivo approaches will be investigated.Aim 2b: we will develop new mice with altered activity of the TMPRSS2 protease, which enhances SARS-CoV-2 entry into target cells. We aim to identify conditions of improved infectivity in vitro that would lead to better mimic severe clinical COVID-19 symptoms in vivo. Approaches will include expression of hTMPRSS2, deletion of endogenous inhibitors and modeling chronic lung disease.Overall, our project will lead to novel tools for accelerated development of interventions such as antiviral drugs, vaccines and immuno-prophylaxis to halt the current SARS-CoV-2 pandemic outbreak. The developed tools will likely have a significant impact on understanding the pathogenesis of the virus and provide multiple options for much needed pre-clinical applications.

Publicationslinked via Europe PMC

Neutrophil proteases are protective against SARS-CoV-2 by degrading the spike protein and dampening virus-mediated inflammation.

An adjustable, safe and highly protective live-attenuated SARS-CoV-2 vaccine based on large-scale one-to-stop codon modifications

The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype.

Optimized intramuscular immunization with VSV-vectored spike protein triggers a superior protective humoral immune response to SARS-CoV-2

Optimized intramuscular immunization with VSV-vectored spike protein triggers a superior immune response to SARS-CoV-2.

Establishment of well-differentiated camelid airway cultures to study Middle East respiratory syndrome coronavirus.

The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype

Enhanced fitness of SARS-CoV-2 variant of concern Alpha but not Beta.

Establishment of well-differentiated camelid airway cultures to study Middle East respiratory syndrome coronavirus