tetano
Editor, Senior Moderator
J Virol
. 2024 Oct 29:e0130524.
doi: 10.1128/jvi.01305-24. Online ahead of print. Acquisition of a multibasic cleavage site does not increase MERS-CoV entry into Calu-3 human lung cells
Markus Hoffmann[SUP] 1 2 [/SUP], Hannah Kleine-Weber[SUP] 1 2 [/SUP], Luise Graichen[SUP] 1 [/SUP], Inga Nehlmeier[SUP] 1 [/SUP], Amy Kempf[SUP] 1 2 [/SUP], Anna-Sophie Moldenhauer[SUP] 1 [/SUP], Elisabeth Braun[SUP] 3 [/SUP], Abdullah M Assiri[SUP] 4 [/SUP], Frank Kirchhoff[SUP] 3 [/SUP], Daniel Sauter[SUP] 3 5 [/SUP], Khaled R Alkharsah[SUP] 6 [/SUP], Stefan Pöhlmann[SUP] 1 2 [/SUP]
Affiliations
Human-to-human transmission of the highly pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV) is currently inefficient. However, there is concern that the virus might mutate and thereby increase its transmissibility and thus pandemic potential. The pandemic SARS-CoV-2 depends on a highly cleavable furin motif at the S1/S2 site of the viral spike (S) protein for efficient lung cell entry, transmission, and pathogenicity. Here, by employing pseudotyped particles, we investigated whether augmented cleavage at the S1/S2 site also increases MERS-CoV entry into Calu-3 human lung cells. We report that polymorphism T746K at the S1/S2 cleavage site or optimization of the furin motif increases S protein cleavage but not lung cell entry. These findings suggest that, unlike what has been reported for SARS-CoV-2, a highly cleavable S1/S2 site might not augment MERS-CoV infectivity for human lung cells.IMPORTANCEThe highly cleavable furin motif in the spike protein is required for robust lung cell entry, transmission, and pathogenicity of SARS-CoV-2. In contrast, it is unknown whether optimization of the furin motif in the spike protein of the pre-pandemic MERS-CoV increases lung cell entry and allows for robust human-human transmission. The present study indicates that this might not be the case. Thus, neither a naturally occurring polymorphism that increased MERS-CoV spike protein cleavage nor artificial optimization of the cleavage site allowed for increased spike-protein-driven entry into Calu-3 human lung cells.
Keywords: MERS-CoV; cleavage; furin; protease; spike.
. 2024 Oct 29:e0130524.
doi: 10.1128/jvi.01305-24. Online ahead of print. Acquisition of a multibasic cleavage site does not increase MERS-CoV entry into Calu-3 human lung cells
Markus Hoffmann[SUP] 1 2 [/SUP], Hannah Kleine-Weber[SUP] 1 2 [/SUP], Luise Graichen[SUP] 1 [/SUP], Inga Nehlmeier[SUP] 1 [/SUP], Amy Kempf[SUP] 1 2 [/SUP], Anna-Sophie Moldenhauer[SUP] 1 [/SUP], Elisabeth Braun[SUP] 3 [/SUP], Abdullah M Assiri[SUP] 4 [/SUP], Frank Kirchhoff[SUP] 3 [/SUP], Daniel Sauter[SUP] 3 5 [/SUP], Khaled R Alkharsah[SUP] 6 [/SUP], Stefan Pöhlmann[SUP] 1 2 [/SUP]
Affiliations
- PMID: 39470207
- DOI: 10.1128/jvi.01305-24
Human-to-human transmission of the highly pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV) is currently inefficient. However, there is concern that the virus might mutate and thereby increase its transmissibility and thus pandemic potential. The pandemic SARS-CoV-2 depends on a highly cleavable furin motif at the S1/S2 site of the viral spike (S) protein for efficient lung cell entry, transmission, and pathogenicity. Here, by employing pseudotyped particles, we investigated whether augmented cleavage at the S1/S2 site also increases MERS-CoV entry into Calu-3 human lung cells. We report that polymorphism T746K at the S1/S2 cleavage site or optimization of the furin motif increases S protein cleavage but not lung cell entry. These findings suggest that, unlike what has been reported for SARS-CoV-2, a highly cleavable S1/S2 site might not augment MERS-CoV infectivity for human lung cells.IMPORTANCEThe highly cleavable furin motif in the spike protein is required for robust lung cell entry, transmission, and pathogenicity of SARS-CoV-2. In contrast, it is unknown whether optimization of the furin motif in the spike protein of the pre-pandemic MERS-CoV increases lung cell entry and allows for robust human-human transmission. The present study indicates that this might not be the case. Thus, neither a naturally occurring polymorphism that increased MERS-CoV spike protein cleavage nor artificial optimization of the cleavage site allowed for increased spike-protein-driven entry into Calu-3 human lung cells.
Keywords: MERS-CoV; cleavage; furin; protease; spike.