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

• Forschungsstelle: IVI
• Projektnummer: 7270295

Kurzbeschreibung (Deutsch)

Durch den SNF gefördertes Projekt: SNF | P3 Forschungsdatenbank | Project 196062
Die Pandemie der Coronavirus-Krankheit 2019 (COVID-19) hat in der modernen Welt eine beispiellose gesundheitliche, wirtschaftliche und gesellschaftliche Krise ausgelöst. Der Einsatz von wirksamen Impfstoffen und Heilmittel gegen diese Krankheit erfordert, dass neue Modelle entwickelt, um ihre Wirksamkeit zu untersuchen, bevor sie bei Patienten angewendet werden.

Abstract (Englisch)

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-2
Aim 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.