The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways
| Autor: | Lieve Naesens, Dominique Van Looveren, Valerie Raeymaekers, Katleen Martens, Annelies Stevaert, Manon Laporte, Stefan Pöhlmann, Hendrik Jan Thibaut, Piet Maes, Isabel Marchand-Casas, Markus Hoffmann, Ria Van Berwaer, Julie Vandeput |
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| Rok vydání: | 2021 |
| Předmět: |
RNA viruses
Viral Diseases Coronaviruses viruses Respiratory System Virus Replication medicine.disease_cause Biochemistry Medical Conditions 0302 clinical medicine Coronavirus 229E Human Biology (General) Furin Pathology and laboratory medicine Coronavirus 0303 health sciences biology Serine Endopeptidases Temperature virus diseases Proteases Medical microbiology Enzymes Cell biology Infectious Diseases Viruses Spike Glycoprotein Coronavirus Middle East Respiratory Syndrome Coronavirus SARS CoV 2 Pathogens Research Article Viral Entry SARS coronavirus QH301-705.5 Immunology Context (language use) Transfection Research and Analysis Methods Microbiology Virus 03 medical and health sciences Viral entry Virology Genetics medicine Humans Molecular Biology Techniques Molecular Biology Tropism 030304 developmental biology Medicine and health sciences Biology and life sciences SARS-CoV-2 Organisms Viral pathogens Proteins COVID-19 Membrane Proteins Covid 19 RC581-607 Virus Internalization Viral Replication Microbial pathogens Viral replication Enzymology biology.protein Parasitology Immunologic diseases. Allergy Viral Transmission and Infection 030217 neurology & neurosurgery Peptide Hydrolases |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 17, Iss 4, p e1009500 (2021) |
| Popis: | The high transmissibility of SARS-CoV-2 is related to abundant replication in the upper airways, which is not observed for the other highly pathogenic coronaviruses SARS-CoV and MERS-CoV. We here reveal features of the coronavirus spike (S) protein, which optimize the virus towards the human respiratory tract. First, the S proteins exhibit an intrinsic temperature preference, corresponding with the temperature of the upper or lower airways. Pseudoviruses bearing the SARS-CoV-2 spike (SARS-2-S) were more infectious when produced at 33°C instead of 37°C, a property shared with the S protein of HCoV-229E, a common cold coronavirus. In contrast, the S proteins of SARS-CoV and MERS-CoV favored 37°C, in accordance with virus preference for the lower airways. Next, SARS-2-S-driven entry was efficiently activated by not only TMPRSS2, but also the TMPRSS13 protease, thus broadening the cell tropism of SARS-CoV-2. Both proteases proved relevant in the context of authentic virus replication. TMPRSS13 appeared an effective spike activator for the virulent coronaviruses but not the low pathogenic HCoV-229E virus. Activation of SARS-2-S by these surface proteases requires processing of the S1/S2 cleavage loop, in which both the furin recognition motif and extended loop length proved critical. Conversely, entry of loop deletion mutants is significantly increased in cathepsin-rich cells. Finally, we demonstrate that the D614G mutation increases SARS-CoV-2 stability, particularly at 37°C, and, enhances its use of the cathepsin L pathway. This indicates a link between S protein stability and usage of this alternative route for virus entry. Since these spike properties may promote virus spread, they potentially explain why the spike-G614 variant has replaced the early D614 variant to become globally predominant. Collectively, our findings reveal adaptive mechanisms whereby the coronavirus spike protein is adjusted to match the temperature and protease conditions of the airways, to enhance virus transmission and pathology. Author summary The devastating COVID-19 pandemic is caused by SARS-CoV-2, a novel virus that despite recent zoonotic introduction is already very well adapted to its human host. Its rapid spread is related to abundant replication in the upper airways, which is not observed for other highly pathogenic human coronaviruses. To understand the role of the viral spike protein in this airway adaptation, we constructed pseudoviruses of SARS-CoV-2 and other coronaviruses that cause severe pneumonia or, on the contrary, a mild common cold. The key findings were verified with authentic virus. We reveal features of the spike proteins, which optimize the coronavirus towards specific parts of the respiratory tract. Namely, we show that the spike proteins exhibit intrinsic temperature preference to precisely match the upper (~33°C) or lower (37°C) airways. We recognized which proteases of human airways activate the spike for virus entry, in particular one protease that may mediate coronavirus virulence. Finally, a link was perceived between spike stability and entry via endosomal proteases. We propose that these mechanisms of spike fine-tuning may have contributed to a global shift in SARS-CoV-2 epidemiology, from the early spike-D614 to the currently predominating G614 variant. |
| Databáze: | OpenAIRE |
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