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Fribourg et al., (2014). Dynamics of viral antagonism and innate immune response.

May 2015, model of the month by Florent Yvon
Original models: BIOMD0000000528, BIOMD0000000529.


Introduction:

Influenza is a common infectious disease in Humans caused by the influenza virus. About 3 to 5 million severe cases are estimated every year of which 250,000 to 500,000 cases lead to death [1]. Influenza virus is classified into 3 different types, with type A being the most virulent. This virus is subject to high variability, reflected in the host immune response in the early stages of the infection.

Among the cells involved in the innate immune response, the dentritic cells have the capability to trigger and direct the adaptive cell-mediated immune response. This means that the inner variation of the dentritic cells in the immune reponse will have a sensitive influence on the next stages of the immune response.

The detection of the virus triggers the induction of IFNβ, a gene that is part of the interferon. The interferon activates a group of genes called the ISGs (interferon-stimulated genes), leading to the establishment of an antiviral state of the cell.

The influenza virus interferes with the host defense mechanisms via the multifunctionnal protein NS1. This proteins delays viral detection, as well as preventing the activation of the ISGs within the host cell.


The model:

The authors have modelled the interplay between the dentritic cell and two different influenza A H1N1 viruses, A/California/4/2009 and A/New Caledonia/20/1999. The molecular actors involved in these models are shown in figure 1.

The model includes twelve equations expressing the level of gene products that belong to the host cell. Two factors, IC1 and IC2 are added to these equations. IC1 corresponds to the antagonism by NS1 of the virus detection and thus the induction of the interferon. IC2 corresponds to the inhibition of the nuclear pre-mRNA processing and export, also performed by NS1.


Results:

The authors fitted the parameters with the experimental values. This allowed them to compare the 2 strains. The antagonism factor was calculated for IC1 and IC2, separately and cumulatively. The results are shown in figure 2.

Figure 2

Figure 2Antagonism effect of NS1 over time for the 2 viruses. The lower the factor, the stronger the antagonism. Figure taken from [2].


Figure 1

Figure 1Actors in the model from the context of the innate immune response network. The points where the NS1 antagonism is applied are shown with dotted circles. Figure taken from [2].

The mRNA production is inhibited by the NC/99 strain, while the effect is null for Cal/09. Also, the antagonism is effective more quickly in NC/99. It is also much stronger in long-time range, especially with the accumulation of IC1 and IC2, as production terms are multiplied by both factors in the equations.

The simulations of the model allowed the comparison of the 2 viruses in the productions of key mRNAs in the innate immune response. The results are shown on figure 3.

Figure 3

Figure 3Comparison of some mRNA production levels after infection by NC/99 or Cal/09. Simulations are represented by solid lines, while experimental results are represented by dotted lines. Figure taken from [2].

The relevant observations are as follows:

  • Cal/09 applies only a weak antagonism on IFNβ induction
  • NC/99 applies a strong antagonism on both IFNβ induction and mRNA production
  • Globally, the NC/99 antagonism on the interferon induction is stronger that observed in Cal/09.

Conclusion:

The authors have highlighted the temporal behaviour of the innate immune system in response to 2 different influenza A H1N1 viruses. They showed that the NC/99 strain is more efficient than Cal/09 in the antagonism of the innate immune response. They also established a quantitative way to measure and compare the antagonism of each strain. This model, focusing on NS1 antagonism dynamics, highlights a potential new criterion for the classification of influenza viruses.

Bibliographic references

  1. World Health Organization. Influenza (seasonal), Fact Sheet n°211, March 2014.
  2. Fribourg et al. Model of influenza A virus infection: Dynamics of viral antagonism and innate immune response. Journal of Theoretical Biology (2014) Volume 351, 21 June 2014, Pages 47–57
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