Degradation of M1-vRNP complexes in the nucleus
Bioprocess Engineering Group, Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany
free high-affinity binding sites (sites)
virions in the extracellular medium (virions)
Degradation of M1-vRNP complexes in the cytoplasm
virions attached to high-affinity binding sites (virions)
total amount of cRNA in the cell considering an arbitrary segment (molecules)
Binding of virions to high-affinity sites
Heldt2012 - Influenza Virus Replication The model describes the life cycle of influenza A virus in a mammalian cell including the following steps: attachment of parental virions to the cell membrane, receptor-mediated endocytosis, fusion of the virus envelope with the endosomal membrane, nuclear import of vRNPs, viral transcription and replication, translation of the structural viral proteins, nuclear export of progeny vRNPs and budding of new virions. It also explicitly accounts for the stabilization of cRNA by viral polymerases and NP and the inhibition of vRNP activity by M1 protein binding. In short, the model focuses on the molecular mechanism that controls viral transcription and replication. This model is described in the article: Modeling the intracellular dynamics of influenza virus replication to understand the control of viral RNA synthesis. Heldt FS, Frensing T, Reichl U. J Virol. Abstract: Influenza viruses transcribe and replicate their negative-sense RNA genome inside the nucleus of host cells via three viral RNA species. In the course of an infection, these RNAs show distinct dynamics, suggesting that differential regulation takes place. To investigate this regulation in a systematic way, we developed a mathematical model of influenza virus infection at the level of a single mammalian cell. It accounts for key steps of the viral life cycle, from virus entry to progeny virion release, while focusing in particular on the molecular mechanisms that control viral transcription and replication. We therefore explicitly consider the nuclear export of viral genome copies (vRNPs) and a recent hypothesis proposing that replicative intermediates (cRNA) are stabilized by the viral polymerase complex and the nucleoprotein (NP). Together, both mechanisms allow the model to capture a variety of published data sets at an unprecedented level of detail. Our findings provide theoretical support for an early regulation of replication by cRNA stabilization. However, they also suggest that the matrix protein 1 (M1) controls viral RNA levels in the late phase of infection as part of its role during the nuclear export of viral genome copies. Moreover, simulations show an accumulation of viral proteins and RNA toward the end of infection, indicating that transport processes or budding limits virion release. Thus, our mathematical model provides an ideal platform for a systematic and quantitative evaluation of influenza virus replication and its complex regulation. With the current parameter set, the model reproduces an infection at a multiplicity of infection (MOI) of 10. Figure 2A of the paper is reproduced here, with parameters kDegRnp and kSynP changed to zeros. Initial conditions and parameter changes that were used to obtain specific figures in the article can be found in Table A2. The model has the correct value for kAttLo as 4.55e-04. The value of this parameter mentioned as 4.55e-02 in Table 1 of the paper is incorrect. This is checked with the author. This model is hosted on BioModels Database and identified by: MODEL1307270000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.
M1-vRNP complexes in the cytoplasm (virions)
M1-vRNP complexes in the nucleus (virions)
Endocytosis of virions bound to high-affinity sites
synthesis rate of segment 3's mRNA (1/h)
Binding of virions to low-affinity sites
synthesis rate of segment 2's mRNA (1/h)
synthesis rate of segment 1's mRNA (1/h)
Endocytosis of virions bound to low-affinity sites
synthesis rate of segment 6's mRNA (1/h)
combined rate of NEP binding to M1-vRNP complexes and subsequent transport out of the nucleus (1/(molecule*h))
endocytosis rate of virions bound to high-affinity or low-affinity binding sites (1/h)
synthesis rate of segment 7's mRNA (1/h)
complex of viral polymerase and cRNA (molecules)
binding rate of M1 to nuclear vRNPs (1/(h*molecule))
dissociation rate of virions from low-affinity binding sites (1/h)
synthesis rate of segment 4's mRNA (1/h)
complex of viral polymerase and vRNA (molecules)
formation rate of functional polymerase complexes from the three subunits (1/(h*molecule^2))
dissociation rate of virions from high-affinity binding sites (1/h)
synthesis rate of segment 5's mRNA (1/h)
fraction of protein synthesis rate and distance between two adjacent ribosomes (1/h)
attachment rate of virus particles to low-affinity binding sites (1/(site*h))
equilibrium constant for the attachment of virions to the low-affinity binding sites (1/site)
total amount of released virions (virions)
parental vRNPs in the cytoplasm (virions)
nuclear import rate of cytoplasmic vRNPs which are not bound to M1 (1/h)
total amount of cRNA in the cell considering all segments (molecules)
release rate of progeny virions from the cell (virions/(molecule*h))
synthesis rate of segment 8's mRNA (1/h)
degradation rate of virions which do not fuse with the endosomal membrane (1/h)
equilibrium constant for the attachment of virions to the high-affinity binding sites (1/site)
fraction of spliced NEP mRNAs compared to total mRNAs of segment 8 (-)
fusion rate of virions in late endosomes (1/h)
fraction of spliced M2 mRNAs compared to total mRNAs of segment 7 (-)
length of segment 6's mRNA encoding NA (nucleotides)
virions attached to low-affinity binding sites (virions)
distance between two adjacent ribosomes on an mRNA (nucleotides)
length of segment 5's mRNA encoding NP (nucleotides)
synthesis rate of proteins (nucleotides/h)
length of segment 8's unspliced mRNA encoding NS1 (nucleotides)
fraction of fusion-competent virions (-)
total amount of virions fused with endosomes (virions)
length of segment 7's unspliced mRNA encoding M1 (nucleotides)
degradation rate of RdRp-cRNA and RdRp-vRNA complexes (1/h)
attachment rate of virus particles to high-affinity binding sites (1/(site*h))
length of segment 2's mRNA encoding PB1 (nucleotides)
total amount of vRNA in the cell considering an arbitrary segments (molecules)
length of segment 1's mRNA encoding PB2 (nucleotides)
binding rate of NP to RdRp-cRNA and RdRp-vRNA complexes (1/(h*molecule))
total amount of vRNA in the cell considering all segments (molecules)
degradation rate of nascent cRNA and vRNA (1/h)
length of segment 4's mRNA encoding HA (nucleotides)
binding rate of polymerase complexes to cRNA and vRNA (1/(h*molecule))
length of segment 3's mRNA encoding PA (nucleotides)