Characterization of host cell factors used by emerging coronaviruses for entry into target cells

by Hannah Kleine-Weber
Doctoral thesis
Date of Examination:2020-07-14
Date of issue:2020-07-24
Advisor:Prof. Dr. Stefan Pöhlmann
Referee:Prof. Dr. Stefan Pöhlmann
Referee:Prof. Dr. Uwe Groß
Referee:Prof. Dr. Friedemann Weber
Persistent Address: http://dx.doi.org/10.53846/goediss-8112

 

 

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Abstract

English

Human coronaviruses (HCoV) mainly cause common cold-like symptoms. However, in the last two decades the emerging coronaviruses the severe acute respiratory syndrome coronavirus (SARS-CoV) (in 2002), Middle East respiratory syndrome coronavirus (MERS-CoV) (in 2014) and SARS-CoV-2 (in 2019) were introduced into the human population from animal reservoirs and were found to cause severe disease. Novel antiviral strategies are required to combat these viruses particularly the pandemic SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). Coronaviruses harbor a spike glycoprotein (S) in their envelope, which is responsible for host cell entry. Entry depends on S protein interactions with cellular receptors and on S protein activation by host cell proteases. The goal of this thesis was to identify these interaction partners and to characterize these interactions on the molecular level, with the ultimate goal to identify targets for antiviral intervention. The thesis work revealed that MERS-CoV and SARS-CoV-2 S proteins depend on furin-mediated cleavage at the so called S1/S2 site for subsequent S protein cleavage at the S2’ site, which results in S protein activation for entry into human lung cells. Moreover, the results of this thesis show that polymorphisms in the S protein of MERS-CoV can protect the virus against antibody mediated neutralization and that polymorphisms in the viral receptor dipeptidyl peptidase 4 (DPP4), modulate entry efficiency. Finally, it was uncovered that SARS-CoV-2, like SARS-CoV, employs angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease subtype 2 (TMPRSS2) for entry into lung cells and evidence was provided that the clinically proven TMPRSS2 inhibitor camostat mesylate could be used for COVID-19 treatment. In sum, the study provided key insights into host cell entry of MERS-CoV and SARS-CoV-2 and defined TMPRSS2 as target for intervention
Keywords: coronaviruses
 
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