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

Lopacinski, Aaron B.; Sweatt, Andrew J.; Smolko, Christian; Gray-Gaillard, Elise; Borgman, Cheryl A.; Shah, Millie; Janes, Kevin A.

doi:10.1016/j.cels.2021.02.004

Cited by 16 publications

(30 citation statements)

References 121 publications

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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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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 virus was propagated in HeLa cells. Viral titers were determined using the plaque assay [ 77 ]. SH-SY5Y cells were incubated with CVB3 at the 1 multiplicity of infection (MOI) in serum-free DMEM for 1 h and further incubated in DMEM supplemented with 10% FBS for 30 h. For primary neurons, cells were incubated with the indicated MOI of CVB3 in neuron culture medium for 24 h. In the in vivo model, 8- to 11- week-old male mice were infected by intraperitoneal (IP) injection with 1.0 × 10 6 plaque forming units (PFUs) of CVB3 in 100 μl of phosphate-buffered saline (PBS).…”

Section: Methodsmentioning

confidence: 99%

Interaction between coxsackievirus B3 infection and α-synuclein in models of Parkinson’s disease

2021

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Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. PD is pathologically characterized by the death of midbrain dopaminergic neurons and the accumulation of intracellular protein inclusions called Lewy bodies or Lewy neurites. The major component of Lewy bodies is α-synuclein (α-syn). Prion-like propagation of α-syn has emerged as a novel mechanism in the progression of PD. This mechanism has been investigated to reveal factors that initiate Lewy pathology with the aim of preventing further progression of PD. Here, we demonstrate that coxsackievirus B3 (CVB3) infection can induce α-syn-associated inclusion body formation in neurons which might act as a trigger for PD. The inclusion bodies contained clustered organelles, including damaged mitochondria with α-syn fibrils. α-Syn overexpression accelerated inclusion body formation and induced more concentric inclusion bodies. In CVB3-infected mice brains, α-syn aggregates were observed in the cell body of midbrain neurons. Additionally, α-syn overexpression favored CVB3 replication and related cytotoxicity. α-Syn transgenic mice had a low survival rate, enhanced CVB3 replication, and exhibited neuronal cell death, including that of dopaminergic neurons in the substantia nigra. These results may be attributed to distinct autophagy-related pathways engaged by CVB3 and α-syn. This study elucidated the mechanism of Lewy body formation and the pathogenesis of PD associated with CVB3 infection.

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“…However, most computational models have limited documentation and require knowledge of structured programming to operate. To overcome this barrier for non-computationalists, we developed a graphical user interface (GUI) version of a publicly available model of coxsackievirus B3 (CVB3) infection ( Lopacinski et al., 2021 ). CVB3 is a member of the Picornavirus family of non-enveloped, positive-strand RNA viruses.…”

Section: Before You Beginmentioning

confidence: 99%

“…The model simplifies some viral life cycle processes to improve interpretability and utility when performing in silico experiments. For complete details on the use and execution of this protocol, please refer to Lopacinski et al. (2021) .…”

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Simulating coxsackievirus B3 infection with an accessible computational model of its complete kinetics

2021

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

Cited by 16 publications

References 121 publications

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

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

Interaction between coxsackievirus B3 infection and α-synuclein in models of Parkinson’s disease

Simulating coxsackievirus B3 infection with an accessible computational model of its complete kinetics

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