Noise-induced bistability in the quasi-neutral coexistence of viral RNAs under different replication modes

[EN] Evolutionary and dynamical investigations into real viral populations indicate that RNA replication can range between the two extremes represented by so-called 'stamping machine replication' (SMR) and 'geometric replication' (GR). The impact of asymmetries in replication for single-stranded (+) sense RNA viruses has been mainly studied with deterministic models. However, viral replication should be better described by including stochasticity, as the cell infection process is typically initiated with a very small number of RNA macromolecules, and thus largely influenced by intrinsic noise. Under appropriate conditions, deterministic theoretical descriptions of viral RNA replication predict a quasi-neutral coexistence scenario, with a line of fixed points involving different strands' equilibrium ratios depending on the initial conditions. Recent research into the quasi-neutral coexistence in two competing populations reveals that stochastic fluctuations fundamentally alter the mean-field scenario, and one of the two species outcompetes the other. In this article, we study this phenomenon for viral RNA replication modes by means of stochastic simulations and a diffusion approximation. Our results reveal that noise has a strong impact on the amplification of viral RNAs, also causing the emergence of noise-induced bistability. We provide analytical criteria for the dominance of (+) sense strands depending on the initial populations on the line of equilibria, which are in agreement with direct stochastic simulation results. The biological implications of this noise-driven mechanism are discussed within the framework of the evolutionary dynamics of RNA viruses with different modes of replication.The research leading to these results has received funding from 'la Caixa' Foundation. J.S. and T.A. have been partially funded by the CERCA Program of the Generalitat de Catalunya, MINECO grant no. MTM2015-71509-C2-1-R and by a MINECO grant awarded to the Barcelona Graduate School of Mathematics under the 'Maria de Maeztu' Program (grant no. MDM-2014-0445). T.A. is also supported by AGAUR (grant no. 2014SGR1307). S.F.E. has been supported by MINECO-FEDER grant no. BFU2015-65037-P and by Generalitat Valenciana grant no. PROMETEOII/2014/021.Sardanyes, J.; Arderiu, A.; Elena Fito, SF.; Alarcon, T. (2018). Noise-induced bistability in the quasi-neutral coexistence of viral RNAs under different replication modes. Journal of The Royal Society Interface. 15(142):1-10. https://doi.org/10.1098/rsif.2018.0129S11015142Sardanyés, J., Solé, R. V., & Elena, S. F. (2009). Replication Mode and Landscape Topology Differentially Affect RNA Virus Mutational Load and Robustness. Journal of Virology, 83(23), 12579-12589. doi:10.1128/jvi.00767-09Thébaud, G., Chadœuf, J., Morelli, M. 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Supplementary info from Noise-induced bistability in the quasi-neutral coexistence of viral RNAs under different replication modes. 21 February 2018 8 May 2018

Evolutionary and dynamical investigations into real viral populations indicate that RNA replication can range between the two extremes represented by the so-called ‘stamping machine replication’ (SMR) and ‘geometric replication’ (GR). The impact of asymmetries in replication for single stranded, (+) sense RNA viruses has been mainly studied with deterministic models. However, viral replication should be better described by including stochasticity, as the cell infection process is typically initiated with a very small number of RNA macromolecules, and thus largely influenced by intrinsic noise. Under appropriate conditions, deterministic theoretical descriptions of viral RNA replication predict a quasi-neutral coexistence scenario, with a line of fixed points involving different strands' equilibrium ratios depending on the initial conditions. Recent research into the quasi-neutral coexistence in two competing populations reveals that stochastic fluctuations fundamentally alter the mean-field scenario, and one of the two species outcompetes the other one. In this manuscript, we study this phenomenon for viral RNAs replication modes by means of stochastic simulations and a diffusion approximation. Our results reveal that noise has a strong impact on the amplification of viral RNAs, also causing the emergence of noise-induced bistability. We provide analytical criteria for the dominance of (+) sense strands depending on the initial populations on the line of equilibria, which are in agreement with direct stochastic simulation results. The biological implications of this noise-driven mechanism are discussed within the framework of the evolutionary dynamics of RNA viruses with different modes of replication

Sustained Endothelial Expression of HoxA5 In Vivo Impairs Pathological Angiogenesis And Tumor Progression

HoxA5 is expressed in quiescent endothelial cells (EC), but absent in activated angiogenic EC. To examine the efficacy of targeting HoxA5 therapeutically to quell pathologic or tumor angiogenesis, we generated an inducible, transgenic mouse model of sustained HoxA5 expression in ECs. During pathologic angiogenesis, sustained HoxA5 regulates expression several angiogenic effector molecules, notably increased expression of TSP-2 and reduced expression of VEGF, thus leading to inhibition of pathological angiogenesis in tissues. To evaluate if this impressive reduction of vascularization could also impact tumor angiogenesis, HoxA5 mice were bred with a mouse model of de novo squamous carcinogenesis, e.g., K14-HPV16 mice. Activation of EC-HoxA5 significantly reduced infiltration by mast cells into neoplastic skin, an early hallmark of progression to dysplasia, reduced angiogenic vasculature, and blunted characteristics of tumor progression. To evaluate HoxA5 as a therapeutic, topical application of a HoxA5 transgene onto early neoplastic skin of K14-HPV16 mice similarly resulted in a significant impairment of angiogenic vasculature and progression to dysplasia to a similar extent as observed with genetic delivery of HoxA5. Together these data indicate that HoxA5 represents a novel molecule for restricting pathological and tumorigenic angiogenesis