A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection

Zitzmann, Carolin; Schmid, Bianca; Ruggieri, Alessia; Perelson, Alan S.; Binder, Marco; Bartenschlager, Ralf; Kaderali, Lars

doi:10.3389/fmicb.2020.00725

Cited by 30 publications

(63 citation statements)

References 83 publications

(113 reference statements)

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“…Applying the drug effect to the transition rate between phases does lead to a decrease in the decay rate as well as a slight decrease in viral peak, so this seems to be the most likely candidate for mathematically modeling the effect of remdesivir. It is also possible to construct even more detailed mathematical models that include intracellular processes ( Zitzmann et al, 2020 ; Heldt et al, 2013 ) in order to apply the drug effect in a manner that more closely reflects the biological reality. Unfortunately, in order to properly parameterize a model that includes all these extra details, we need more than just viral titer measurements ( Heldt et al, 2013 ; Miao et al, 2011 ), so it is not possible to test such models with the current data set.…”

Section: Discussionmentioning

confidence: 99%

Quantifying the effect of remdesivir in rhesus macaques infected with SARS-CoV-2

Dobrovolny

2020

Virology

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The world is in the midst of a pandemic caused by a novel coronavirus and is desperately searching for possible treatments. The antiviral remdesivir has shown some effectiveness against SARS-CoV-2 in vitro and in a recent animal study. We use data from a study of remdesivir in rhesus macaques to fit a viral kinetics model in an effort to determine the most appropriate mathematical descripton of the effect of remdesivir. We find statistically significant differences in the viral decay rate and use this to inform a possible mathematical formulation of the effect of remdesivir. Unfortunately, this model formulation suggests that the application of remdesivir will lengthen SARS-CoV-2 infections, putting into question its potential clinical benefit.

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Section: Discussionmentioning

confidence: 99%

Quantifying the effect of remdesivir in rhesus macaques infected with SARS-CoV-2

Dobrovolny

2020

Virology

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“…To identify cellular processes that are essential for explaining SARS-CoV-2 replication in our experimental system, we developed a model that was devoid of mechanistic details in contrast to previous ODE-models of RNA virus replication that included aspects as positive and negative RNA strands, virus particle formation or shuttling between cellular compartments (Binder et al, 2013;Aunins et al, 2018;Zitzmann et al, 2020;Lopacinski et al, 2021). Modeling showed that taking into account the inhibition of the transcription of anti-viral response genes by virus proteins was required to explain our experimental dataset.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of SARS-CoV-2 host cell interactions inferred from transcriptome analyses

Adam

Stanifer

Springer

et al. 2021

Preprint

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The worldwide spread of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) caused an urgent need for an in-depth understanding of interactions between the virus and its host. Here, we dissected the dynamics of virus replication and the host cell transcriptional response to SARS-CoV-2 infection at a systems level by combining time-resolved RNA sequencing with mathematical modeling. We observed an immediate transcriptional activation of inflammatory pathways linked to the anti-viral response followed by increased expression of genes involved in ribosome and mitochondria function, thus hinting at rapid alterations in protein production and cellular energy supply. At later stages, metabolic processes, in particular those depending on cytochrome P450 enzymes, were downregulated. To gain a deeper understanding of the underlying transcriptional dynamics, we developed an ODE model of SARS-CoV-2 infection and replication. Iterative model reduction and refinement revealed that a negative feedback from virus proteins on the expression of anti-viral response genes was essential to explain our experimental dataset. Our study provides insights into SARS-CoV-2 virus-host interaction dynamics and facilitates the identification of druggable host pathways supporting virus replication.

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“…For MAVS cleavage, a plausible candidate is the precursor to 3C pro and 3D pol , 3CD pro , which has both protease activity and nucleotide-binding activity for replication (Franco et al, 2005). The importance of potently antagonizing ISG induction is corroborated by a recent computational model of Dengue virus (Zitzmann et al, 2020). Combining the enteroviral life cycle with host-cell feedbacks created a rich dynamical system to mine for predicted behavior that was non-intuitive and possibly important for pathogenesis.…”

Section: Loss Of Type I Interferon Signaling Coincides With Degradatimentioning

confidence: 98%

Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback

et al. 2021

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Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback Graphical abstract Highlights d A complete kinetic model of acute infection by the coxsackievirus B3 enterovirus d Enteroviral replication organelles accelerate biochemistry on membrane surfaces d Type I interferon exaggerates different enteroviral susceptibilities of host cells d A common polymorphism in MAVS alters host-cell susceptibility to coxsackievirus B3

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A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection

Cited by 30 publications

References 83 publications

Quantifying the effect of remdesivir in rhesus macaques infected with SARS-CoV-2

Quantifying the effect of remdesivir in rhesus macaques infected with SARS-CoV-2

Dynamics of SARS-CoV-2 host cell interactions inferred from transcriptome analyses

Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback

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