Modelling how the altered usage of cell entry pathways by the SARS-CoV-2 Omicron variant may affect the efficacy and synergy of TMPRSS2 and Cathepsin B/L inhibitors

Padmanabhan, Pranesh; Dixit, Narendra M.

doi:10.1101/2022.01.13.476267

Cited by 8 publications

(5 citation statements)

References 55 publications

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“…Several recently identified circulating mutants are known to be more infectious/ transmissible than the original SARS-CoV-2 strain and to escape immune responses [115]. These characteristics could be incorporated in our model by suitably increasing the infectivity (e.g., see [116]) and/or decreasing the strength of the immune response, to simulate how emerging strains could alter the overall severity of the infection, which in turn could be tested against data from patients infected by those strains. We recognize that to estimate the effects of such variations at the population level, knowledge of how the parameter values in our model, particularly those defining the innate and CD8 T-cell responses, are distributed across individuals in a population would be required.…”

Section: Plos Pathogensmentioning

confidence: 99%

Modeling recapitulates the heterogeneous outcomes of SARS-CoV-2 infection and quantifies the differences in the innate immune and CD8 T-cell responses between patients experiencing mild and severe symptoms

2022

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SARS-CoV-2 infection results in highly heterogeneous outcomes, from cure without symptoms to acute respiratory distress and death. Empirical evidence points to the prominent roles of innate immune and CD8 T-cell responses in determining the outcomes. However, how these immune arms act in concert to elicit the outcomes remains unclear. Here, we developed a mathematical model of within-host SARS-CoV-2 infection that incorporates the essential features of the innate immune and CD8 T-cell responses. Remarkably, by varying the strengths and timings of the two immune arms, the model recapitulated the entire spectrum of outcomes realized. Furthermore, model predictions offered plausible explanations of several confounding clinical observations, including the occurrence of multiple peaks in viral load, viral recrudescence after symptom loss, and prolonged viral positivity. We applied the model to analyze published datasets of longitudinal viral load measurements from patients exhibiting diverse outcomes. The model provided excellent fits to the data. The best-fit parameter estimates indicated a nearly 80-fold stronger innate immune response and an over 200-fold more sensitive CD8 T-cell response in patients with mild compared to severe infection. These estimates provide quantitative insights into the likely origins of the dramatic inter-patient variability in the outcomes of SARS-CoV-2 infection. The insights have implications for interventions aimed at preventing severe disease and for understanding the differences between viral variants.

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Section: Plos Pathogensmentioning

confidence: 99%

Modeling recapitulates the heterogeneous outcomes of SARS-CoV-2 infection and quantifies the differences in the innate immune and CD8 T-cell responses between patients experiencing mild and severe symptoms

2022

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“…Through genome sequencing analysis, different variants of concern (VOCs) and variants of interest (VOI) have been identified, and different capabilities to exploit the two entry processes have been observed [9][10][11]. This could impact both the cell tropism and the transmissibility, explaining the differences in the spread of the viral variants all over the world [10].…”

Section: Introductionmentioning

confidence: 99%

Proper Selection of In Vitro Cell Model Affects the Characterization of the Neutralizing Antibody Response against SARS-CoV-2

Criscuolo

Giuliani

Ferrarese

et al. 2022

Viruses

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(1) Background: Our aim is the evaluation of the neutralizing activity of BNT162b2 mRNA vaccine-induced antibodies in different in vitro cellular models, as this still represents one of the surrogates of protection against SARS-CoV-2 viral variants. (2) Methods: The entry mechanisms of SARS-CoV-2 in three cell lines (Vero E6, Vero E6/TMPRSS2 and Calu-3) were evaluated with both pseudoviruses and whole virus particles. The neutralizing capability of sera collected from vaccinated subjects was characterized through cytopathic effects and Real-Time RT PCR. (3) Results: In contrast to Vero E6 and Vero E6/TMPRSS2, Calu-3 allowed the evaluation of both viral entry mechanisms, resembling what occurs during natural infection. The choice of an appropriate cellular model can decisively influence the determination of the neutralizing activity of antibodies against SARS-CoV-2 variants. Indeed, the lack of correlation between neutralizing data in Calu-3 and Vero E6 demonstrated that testing the antibody inhibitory activity by using a single cell model possibly results in an inaccurate characterization. (4) Conclusions: Cellular systems allowing only one of the two viral entry pathways may not fully reflect the neutralizing activity of vaccine-induced antibodies moving increasingly further away from possible correlates of protection from SARS-CoV-2 infection.

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“…It demonstrated that each cell lineage has a relative percentage of entry preferential pathway mediated by host proteases to be used by the virus ( Padmanabhan et al, 2020 ). Using the omicron variant (B.1.1.529), another study presented the increase of cathepsin B/L mediated entry compared to other strains ( Padmanabhan and Dixit, 2022 —Preprint). This change in the entry route may impact cells with high expression of TMPRSS2 and explain the lower affinity of this variant for lung cells.…”

Section: Discussionmentioning

confidence: 99%

Limited permissibility of ENL-R and Mv-1-Lu mink cell lines to SARS-CoV-2

et al. 2022

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The SARS-CoV-2 pandemic started in the end of 2019 in Wuhan, China, which highlighted the scenario of frequent cross-species transmission events. From the outbreak possibly initiated by viral spill-over into humans from an animal reservoir, now we face the human host moving globally while interacting with domesticated and peridomestic animals. The emergence of a new virus into the ecosystem leads to selecting forces and species-specific adaptations. The adaptation of SARS-CoV-2 to other animals represents a risk to controlling the dissemination of this coronavirus and the emergence of new variants. Since 2020, several mink farms in Europe and the United States have had SARS-CoV-2 outbreaks with human–mink and mink–human transmission, where the mink-selected variants possibly hold evolutionary concerning advantages. Here we investigated the permissibility of mink lung-derived cells using two cell lines, Mv-1-Lu and ENL-R, against several lineages of SARS-CoV-2, including some classified as variants of concern. The viral release rate and the infectious titers indicate that these cells support infections by different SARS-CoV-2 lineages. The viral production occurs in the first few days after infection with the low viral release by these mink cells, which is often absent for the omicron variant for lung cells. The electron microscopy reveals that during the viral replication cycle, the endomembrane system of the mink-host cell undergoes typical changes while the viral particles are produced, especially in the first days of infection. Therefore, even if limited, mink lung cells may represent a selecting source for SARS-CoV-2 variants, impacting their transmissibility and pathogenicity and making it difficult to control this new coronavirus.

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Modelling how the altered usage of cell entry pathways by the SARS-CoV-2 Omicron variant may affect the efficacy and synergy of TMPRSS2 and Cathepsin B/L inhibitors

Cited by 8 publications

References 55 publications

Modeling recapitulates the heterogeneous outcomes of SARS-CoV-2 infection and quantifies the differences in the innate immune and CD8 T-cell responses between patients experiencing mild and severe symptoms

Modeling recapitulates the heterogeneous outcomes of SARS-CoV-2 infection and quantifies the differences in the innate immune and CD8 T-cell responses between patients experiencing mild and severe symptoms

Proper Selection of In Vitro Cell Model Affects the Characterization of the Neutralizing Antibody Response against SARS-CoV-2

Limited permissibility of ENL-R and Mv-1-Lu mink cell lines to SARS-CoV-2

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