Energy dynamics for systemic configurations of virus-host co-evolution

Abstract

ArticlePositive single-stranded RNA ((+)ssRNA) viruses, including picornaviruses, flaviviruses, togaviridae and human coronaviruses (h-CoVs) 1-4 cause multiple outbreaks, for which tailored antiviral strategies are still missing [5][6][7] . (+)ssRNA viruses package their genomes as messenger sense, single stranded RNA and replicate those genomes solely through RNA intermediates in the cytosol of the host cells 8 . RNA-dependent RNA polymerases lack co-and post-replicative fidelity-enhancing pathways, and final RNA genome copies incorporate mutations at a much higher rate than that observed for DNA genomes 9,10 providing the viral quasispecies a higher probability to evolve and adapt to new environments and challenges during infection 11,12 . The diversity is essential for both viral fitness and pathogenesis, due to the complex relationship between virus replication, host cells and immune system, since almost +RNA viruses can delay antiviral innate immune response 13 in multiple ways [14][15][16][17][18][19][20] . Host immunogenetic factors can be sensitive to a variation in the viral load, conveying to a defective response of the innate immunity that could explain the variable clinical course of infection 20,21 . Among (+)ssRNA viruses, h-CoVs have unusually large genomes (∼30 kb) associated with low mutation rates 20,22 . Three novel h-CoVs are etiological agents of serious viral interstitial pneumonia 23 . They include the severe acute respiratory syndrome, first described in Guandong province in China in 2002 24 , the Middle East respiratory syndrome (caused by MERS-CoV), emerged in June 2012 in Saudi Arabia and Qatar 25 , and the SARS-CoV-2, emerged in China in January 2020, cause of the largest outbreak in the modern history 23 .Recent studies confirmed the complexity of viral dynamics, whose fitness is improved by the complex interactions with the host proteins 26,27 as previously described in modelling the virus-host interactions at sub-cell and cell levels 6,28-31 . However, models that address a specific aspect of the virus-host interaction do not capture the wide range of intertwined spatial and temporal (hours to days) dynamic scales 32 , that are related to the interaction of different concurrent hierarchical levels.All these factors address the need for a description able to connect all the levels at which the infection proceeds within a single cell, from the recruitment of RNA-synthesis factory to the final host cell damage. Several drugs, such as chloroquine 33,34 , hydroxychloroquine, ribavirin, lopinavir-ritonavir 35 , were used in patients with SARS [33][34][35] or MERS 7 and are currently under investigation, alone or in combination, to control the COVID-19 infection [36][37][38][39][40][41][42][43][44][45][46][47] . However, there is an urgent need of a new class of compounds, other than nucleotides mimetics, due their low-fidelity viral RNA polymerase 48 to combine with host factor targeting agents, recently identified to lead to a therapeutic regimen to treat COVID-19 6 .We show that, b...