Mutations in SARS-CoV-2 variants of concern link to increased spike cleavage and virus transmission

Escalera, Alba; Gonzalez‐Reiche, Ana S.; Aslam, Sadaf; Mena, Ignacio; Laporte, Manon; Pearl, Raymond; Fossati, Andrea; Rathnasinghe, Raveen; Alshammary, Hala; Guchte, Adriana van de; Farrugia, Keith; Qin, Yiren; Bouhaddou, Mehdi; Kehrer, Thomas; Zuliani-Alvarez, Lorena; Meekins, David A.; Balaraman, Velmurugan; McDowell, Chester; Richt, Jürgen A.; Bajic, Goran; Sordillo, Emilia Mia; Déjosez, Marion; Zwaka, Thomas P.; Krogan, Nevan J.; Simon, Viviana; Albrecht, Randy A.; Bakel, Harm van; García‐Sastre, Adolfo; Aydillo, Teresa

doi:10.1016/j.chom.2022.01.006

Cited by 166 publications

(173 citation statements)

References 66 publications

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“…Efficient S1/S2 cleavage of Omicron spike is consistent with this VOC containing the FCS optimising mutations P681H, N679K and H655Y (Fig. 1A) that can enhance S1/S2 cleavage (Escalera et al, 2022; Peacock et al, 2021b). The total amount of cleaved spike in virions (S2/N) was however lower for Omicron compared to other VOCs (Fig.…”

Section: Resultssupporting

confidence: 74%

“…Alpha and Delta have both evolved an optimised FCS, leading to enhanced S1/S2 spike cleavage (Escalera et al, 2022; Lista et al, 2021; Peacock et al, 2021b), with other mutations outside the FCS (i.e. H69/V70 deletion and D614G) also influencing spike cleavage (Escalera et al, 2022; Gobeil et al, 2021; Meng et al, 2021). Therefore, we hypothesised that evolution of these VOCs may have led to, or selected for, evasion from GBPs that we show potently inhibit early-lineage Wuhan-Hu-1.…”

Section: Discussionmentioning

confidence: 99%

“…Much focus has been on spike mutations arising from selective pressure for antibody escape, however SARS-CoV-2 spike continuously adapts in other ways to the human host. This is evidenced by the dominant VOCs which harbour spike mutations near and within the FCS, suggesting potential evolution of an optimised furin cleavage site (Escalera et al, 2022; Peacock et al, 2021b). Alpha and Delta have acquired mutations at position 681 (P681H and P681R respectively).…”

Section: Introductionmentioning

confidence: 99%

“…Omicron has three mutations in this region, P681H, H655Y and N679K. The optimised FCS has been reported to increase spike processing and fusogenicity for Alpha and Delta (Escalera et al, 2022; Peacock et al, 2021a; Rajah et al, 2021; Saito et al, 2022). By contrast, Omicron shows reduced fusion despite containing the same P681H mutation as Alpha (Du et al, 2022; Meng et al, 2022; Peacock et al, 2022; Willett et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…By contrast, Omicron shows reduced fusion despite containing the same P681H mutation as Alpha (Du et al, 2022; Meng et al, 2022; Peacock et al, 2022; Willett et al, 2022). Intriguingly, Omicron, the most recent VOC, appears to also use a TMPRSS2-independent, endosomal entry pathway (Escalera et al, 2022; Meng et al, 2022; Peacock et al, 2022; Shuai et al, 2022; Willett et al, 2022). This distinguishes Omicron from preceding SARS-CoV-2 strains, including early-lineage isolates and VOCs, all of which favour TMPRSS2 usage for infection of naturally permissive human airway cells.…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Spike evolution influences GBP and IFITM sensitivity

Mesner

Reuschl

Whelan

et al. 2022

Preprint

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SARS-CoV-2 spike requires proteolytic processing for viral entry. The presence of a polybasic furin-cleavage site (FCS) in spike, and evolution towards an optimised FCS by dominant variants of concern (VOCs), are linked to enhanced infectivity and transmission. Guanylate binding proteins (GBP) are interferon-inducible restriction factors that target furin-mediated processing of viral envelope proteins and limit infectivity. Here we investigated whether GBPs restrict SARS-CoV-2 infection, and whether VOCs have evolved spikes that escape restriction. We show that GBP2 and 5 interfere with cleavage of the spike proteins of Wuhan-Hu-1, Alpha, Delta and Omicron, consistent with furin inhibition by GBPs. However, while GBP2/5 restrict Wuhan-Hu-1 infectivity, Alpha and Delta escape restriction. GBP exposure in producer cells influences viral entry route into target cells, with a shift towards endosomal entry. We therefore investigated whether GBP-targeting of spike alters sensitivity to endosomal restriction factors, IFITMs. We find IFITM1, but not IFITM 2 or 3, inhibit infection of naturally-permissive epithelial cells by early-lineage SARS-CoV-2, as well as Alpha and Delta, however GBPs did not sensitise to IFITM restriction. Strikingly, we find Omicron is unique amongst VOCs, being sensitive to restriction by GBP2/5, and also IFITM1, 2 and 3. We conclude evolution of Alpha and Delta spikes have conferred resistance to GBP restriction, but this is not solely due to acquisition of an enhanced FCS. Notably, Omicron, which has evolved under different selective pressures, has selected for changes in spike that not only mediate antibody escape, and shift in cell tropism and entry, but also impact the sensitivity of Omicron to innate immunity, potentially contributing to altered pathogenesis.

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Section: Resultssupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Spike evolution influences GBP and IFITM sensitivity

Mesner

Reuschl

Whelan

et al. 2022

Preprint

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Turning point: A new global COVID‐19 wave or a signal of the beginning of the end of the global COVID‐19 pandemic?

Ding

Jiang

Xiong

et al. 2022

Immunity Inflam & Disease

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A new variant named Omicron (B.1.1.529), first identified in South Africa, has become of considerable interest to the World Health Organization. This variant differs from the other known major variants, as it carries a large number of unusual mutations, particularly in the spinous process protein and receptor binding domains. Some specific mutation sites make it vaccine resistant, highly infectious, and highly pathogenic. The world fears that the Omicron variant could be even more harmful than the previous major variant, given that it has emerged amid fierce competition to trigger a new global pandemic peak as infections in South Africa rise. However, some epidemiological evidence has emerged that the Omicron variant may produce milder patient symptoms. We speculate if the virulence of the Omicron variant will diminish as transmissibility increases, thereby signaling the beginning of the end for the global COVID‐19 pandemic. Based on this view, we make recommendations for COVID‐19 mitigation in the present and future. However, it will take a few weeks to determine the true threat posed by the Omicron variant and we need to be fully prepared for future outbreaks, regardless of their severity.

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SARS‐CoV‐2 Spike Protein Induces Time‐Dependent CTSL Upregulation in HeLa Cells and Alveolarspheres

Bolsinger,

Drobny,

Wilfling

et al. 2024

J of Cellular Biochemistry

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Autophagy and lysosomal pathways are involved in the cell entry of SARS‐CoV‐2 virus. To infect the host cell, the spike protein of SARS‐CoV‐2 binds to the cell surface receptor angiotensin‐converting enzyme 2 (ACE2). To allow the fusion of the viral envelope with the host cell membrane, the spike protein has to be cleaved. One possible mechanism is the endocytosis of the SARS‐CoV‐2–ACE2 complex and subsequent cleavage of the spike protein, mainly by the lysosomal protease cathepsin L. However, detailed molecular and dynamic insights into the role of cathepsin L in viral cell entry remain elusive. To address this, HeLa cells and iPSC‐derived alveolarspheres were treated with recombinant SARS‐CoV‐2 spike protein, and the changes in mRNA and protein levels of cathepsins L, B, and D were monitored. Additionally, we studied the effect of cathepsin L deficiency on spike protein internalization and investigated the influence of the spike protein on cathepsin L promoters in vitro. Furthermore, we analyzed variants in the genes coding for cathepsin L, B, D, and ACE2 possibly associated with disease progression using data from Regeneron's COVID Results Browser and our own cohort of 173 patients with COVID‐19, exhibiting a variant of ACE2 showing significant association with COVID‐19 disease progression. Our in vitro studies revealed a significant increase in cathepsin L mRNA and protein levels following exposure to the SARS‐CoV‐2 spike protein in HeLa cells, accompanied by elevated mRNA levels of cathepsin B and D in alveolarspheres. Moreover, an increase in cathepsin L promoter activity was detected in vitro upon spike protein treatment. Notably, the knockout of cathepsin L resulted in reduced internalization of the spike protein. The study highlights the importance of cathepsin L and lysosomal proteases in the SARS‐CoV‐2 spike protein internalization and suggests the potential of lysosomal proteases as possible therapeutic targets against COVID‐19 and other viral infections.

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Mutations in SARS-CoV-2 variants of concern link to increased spike cleavage and virus transmission

Cited by 166 publications

References 66 publications

SARS-CoV-2 Spike evolution influences GBP and IFITM sensitivity

SARS-CoV-2 Spike evolution influences GBP and IFITM sensitivity

Turning point: A new global COVID‐19 wave or a signal of the beginning of the end of the global COVID‐19 pandemic?

SARS‐CoV‐2 Spike Protein Induces Time‐Dependent CTSL Upregulation in HeLa Cells and Alveolarspheres

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