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Social evolution of innate immunity evasion in a virus


Antiviral immunity has been studied extensively from the perspective of virus−cell interactions, yet the role of virus−virus interactions remains poorly addressed. Here, we demonstrate that viral escape from interferon (IFN)-based innate immunity is a social process in which IFN-stimulating viruses determine the fitness of neighbouring viruses. We propose a general and simple social evolution framework to analyse how natural selection acts on IFN shutdown and validate it in cell cultures and mice infected with vesicular stomatitis virus. Furthermore, we find that IFN shutdown is costly because it reduces short-term viral progeny production, thus fulfilling the definition of an altruistic trait. Hence, in well-mixed populations, the IFN-blocking wild-type virus is susceptible to invasion by IFN-stimulating variants and spatial structure consequently determines whether IFN shutdown can evolve. Our findings reveal that fundamental social evolution rules govern viral innate immunity evasion and virulence and suggest possible antiviral interventions.

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Fig. 1: Social evolution model for innate immunity evasion.
Fig. 2: Interaction between VSV WT and Δ51 variants.
Fig. 3: Real-time fluorescence microscopy of VSV WT and Δ51 in MEFs.
Fig. 4: Fitness cost of IFN shutdown.
Fig. 5: Metapopulation structure selects for IFN shutdown.
Fig. 6: Fluorescence microscopy of VSV-infected mouse brains.

Data availability

No restrictions apply to data availability. Relevant data are provided in the manuscript and the Supplementary Information. All data are available from the corresponding author upon request. No new protein, DNA or RNA sequence data, macromolecular structures, crystallographic data or microarray data requiring deposition in public repositories were produced.


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We thank I. Noguera for technical assistance with the animal experiments, J. M. Cuevas, R. Garijo and I. Andreu-Moreno for help with the experimental set up, V. Grdzelishvili for the VSV clones, C. Rivas for the MEFs, and S. West and P. Carazo for helpful discussions. This work was funded by ERC Consolidator Grant 724519 Vis-a-Vis to R.S. P.D.-C. was also funded by a Juan de la Cierva Incorporación postdoctoral contract from the Spanish MINECO.

Author information

Authors and Affiliations



P.D.-C. performed the cell culture experiments. E.S.-O. contributed to designing the model. M.D.-M. performed the animal experiments. R.S. conceived the study, formulated the model, analysed the data and wrote the manuscript.

Corresponding author

Correspondence to Rafael Sanjuán.

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Supplementary information

Supplementary Information

Supplementary Figures 1–6 and Supplementary Table 1.

Reporting Summary

Supplementary Video 1

Progression of a VSV WT–mCherry infection (red) in a MEF culture (phase contrast). The infection spreads until the entire culture is invaded.

Supplementary Video 2

Progression of a VSV Δ51–GFP infection (green) in a MEF culture (phase contrast). The infection spreads from initially infected cells to neighbour cells efficiently, but is subsequently halted by innate immunity.

Supplementary Video 3

Progression of a mixed infection containing both VSV WT–mCherry (red) and VSV Δ51–GFP (green) variants in a MEF culture (phase contrast). The infection spreads from initially infected cells to neighbour cells efficiently, but is subsequently halted by innate immunity. This shows that the presence of the Δ51 variants exerts an inhibitory effect on the WT virus.

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Domingo-Calap, P., Segredo-Otero, E., Durán-Moreno, M. et al. Social evolution of innate immunity evasion in a virus. Nat Microbiol 4, 1006–1013 (2019).

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