Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell

Puray-Chavez, Maritza; LaPak, Kyle M.; Schrank, Travis P.; Elliott, Jennifer L; Bhatt, Dhaval P.; Agajanian, Megan; Jasuja, Ria; Lawson, Dana Q.; Davis, Keanu; Rothlauf, Paul W.; Jo, Heejoon; Lee, Nakyung; Tenneti, Kasyap; Eschbach, Jenna E.; Mugisha, Christian Shema; Vuong, Hung R.; Bailey, Adam L.; Hayes, D. Neil; Whelan, Sean P. J.; Horani, Amjad; Brody, Steven L.; Goldfarb, Dennis; Major, Michael B.; Kutluay, Sebla B.

doi:10.1101/2021.03.01.433431

Cited by 40 publications

(48 citation statements)

References 122 publications

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“…Variant mutations may also confer advantages in an ACE2 independent manner. Indeed, recent work has suggested that the E484 mutation may facilitate viral entry into H522 lung cells, requiring surface heparan sulfates rather than ACE2 (Puray-Chavez et al , 2021). It would be of future interest to examine the syncytia formation potential of the variant mutations in other cell types.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Alpha, Beta and Delta variants display enhanced Spike-mediated Syncytia Formation

Rajah

Hubert

Bishop

et al. 2021

Preprint

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SARS-CoV-2 B.1.1.7 (variant Alpha) and B.1.351 (variant Beta) have supplanted pre-existing strains in many countries. Severe COVID-19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when infected cells fuse with adjacent cells. The fitness, cytopathic effects and type-I interferon (IFN) sensitivity of the variants remain poorly characterized. Here, we assessed B.1.1.7 and B.1.351 spread and fusion in cell cultures. B.1.1.7 and B.1.351 replicated similarly to D614G reference strain in Vero, Caco-2, Calu-3 and primary airway cells and were similarly sensitive to IFN. The variants formed larger and more numerous syncytia. Variant Spikes, in the absence of any other viral proteins, resulted in faster fusion relative to D614G. B.1.1.7 and B.1.351 fusion was similarly inhibited by interferon induced transmembrane proteins (IFITMs). Individual mutations present in the variant Spikes modified fusogenicity, binding to ACE2 and recognition by monoclonal antibodies. Also, B.1.1.7 and B.1.351 variants remain sensitive to innate immunity components. The mutations present in the two variants globally enhance viral fusogenicity and allow for antibody evasion.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Alpha, Beta and Delta variants display enhanced Spike-mediated Syncytia Formation

Rajah

Hubert

Bishop

et al. 2021

Preprint

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“…In the absence of TMPRSS2, SARS-CoV-2 has the flexibility to switch to endosomal entry pathway. Endosomal fusion is the major entry pathway for SARS-CoV-2 in ACE2-deficient cells (20). It is, therefore, of paramount importance for an anti-viral regime to be able to target both pathways.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence to suggest that SARS-CoV-2 uses plasma membrane fusion as the default pathway but can use endosomal fusion if the plasma membrane protease, TMPRSS2, is not available; hence the micro-environment is important in dictating the entry pathway (19). However, it has been found that infection of ACE2-deficient lung cells depends on clathrin-mediated endocytosis and endosomal cathepsin L, indicating that endosomal fusion may well be the major entry pathway in a subset of cell types (20). Endosomal fusion is preceded by receptor-mediated endocytosis and trafficking to an acidic compartment to trigger fusion (10).…”

Section: Introductionmentioning

confidence: 99%

Kite-shaped molecules block SARS-CoV-2 cell entry at a post-attachment step

Chan

Shafi

Ford

2021

Preprint

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Anti-viral small molecules are currently lacking for treating coronavirus infection. The long development timescales for such drugs are a major problem, but could be shortened by repurposing existing drugs. We therefore screened a small library of FDA-approved compounds for potential severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antivirals using a pseudovirus system that allows a sensitive read-out of infectivity. A group of structurally-related compounds, showing moderate inhibitory activity with IC50 values in the 1-5μM range, were identified. Further studies demonstrated that these kite-shaped molecules were surprisingly specific for SARS-CoV and SARS-CoV-2 and that they acted early in the entry steps of the viral infectious cycle, but did not affect virus attachment to the cells. Moreover the compounds were able to prevent infection in both kidney- and lung-derived human cell lines. The structural homology of the hits allowed the production of a well-defined pharmacophore that was found to be highly accurate in predicting the anti-viral activity of the compounds in the screen. We discuss the prospects of repurposing these existing drugs for treating current and future coronavirus outbreaks.

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“…For the sake of completeness, several alternative SARS-CoV-2 host cell receptors/routes (such as neuropilin-1, dipeptidyl peptidase 4, CD147 and clathrin-mediated endocytosis) which may impact tropism of SARS-CoV-2 infection independently of ACE2 have been also described ( Cantuti-Castelvetri et al, 2020 ; Y. J. Li et al, 2020 ; Masre et al, 2020 ; Puray-Chavez et al, 2021 ; Radzikowska et al, 2020 ). These observations suggest that there are additional factors that may participate in COVID-19 progression, which may not be solely reconciled by evaluating ADAM17/ACE2 activities.…”

Section: Sars-cov-induced Ace2 (And Adam17) Zinc-metalloprotease Systemic Hyperactivity As a Possible Pathophysiological Origin Of Covid-mentioning

confidence: 99%

Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?

Montanari

Canonico

Nordi

et al. 2021

Advances in Biological Regulation

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The article describes the possible pathophysiological origin of COVID-19 and the crucial role of renin-angiotensin system (RAS), providing several “converging” evidence in support of this hypothesis. SARS-CoV-2 has been shown to initially upregulate ACE2 systemic activity (early phase), which can subsequently induce compensatory responses leading to upregulation of both arms of the RAS (late phase) and consequently to critical, advanced and untreatable stages of COVID-19 disease. The main and initial actors of the process are ACE2 and ADAM17 zinc-metalloproteases, which, initially triggered by SARS-CoV-2 spike proteins, work together in increasing circulating Ang 1–7 and Ang 1–9 peptides and downstream (Mas and Angiotensin type 2 receptors) pathways with anti-inflammatory, hypotensive and antithrombotic activities. During the late phase of severe COVID-19, compensatory secretion of renin and ACE enzymes are subsequently upregulated, leading to inflammation, hypertension and thrombosis, which further sustain ACE2 and ADAM17 upregulation. Based on this hypothesis, COVID-19-phase-specific inhibition of different RAS enzymes is proposed as a pharmacological strategy against COVID-19 and vaccine-induced adverse effects. The aim is to prevent the establishment of positive feedback-loops, which can sustain hyperactivity of both arms of the RAS independently of viral trigger and, in some cases, may lead to Long-COVID syndrome.

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Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell

Cited by 40 publications

References 122 publications

SARS-CoV-2 Alpha, Beta and Delta variants display enhanced Spike-mediated Syncytia Formation

SARS-CoV-2 Alpha, Beta and Delta variants display enhanced Spike-mediated Syncytia Formation

Kite-shaped molecules block SARS-CoV-2 cell entry at a post-attachment step

Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?

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