Abstract
In the fight against the spread of COVID-19 the emphasis is on vaccination or on reactivating existing drugs used for other purposes. The tight links that necessarily exist between the virus as it multiplies and the metabolism of its host are systematically ignored. Here we show that the metabolism of all cells is coordinated by the availability of a core building block of the cell's genome, cytidine triphosphate (CTP). This metabolite is also the key to the synthesis of the viral envelope and to the translation of its genome into proteins. This unique role explains why evolution has led to the early emergence in animals of an antiviral immunity enzyme, viperin, that synthesizes a toxic analogue of CTP. The constraints arising from this dependency guide the evolution of the virus. With this in mind, we explored the real-time experiment taking place before our eyes using probabilistic modelling approaches to the molecular evolution of the virus. We have thus followed, almost on a daily basis, the evolution of the composition of the viral genome to link it to the progeny produced over time, particularly in the form of blooms that sparked a firework of viral mutations. Some of those certainly increase the propagation of the virus. This led us to make out the critical role in this evolution of several proteins of the virus, such as its nucleocapsid N, and more generally to begin to understand how the virus ties up the host metabolism to its own benefit. A way for the virus to escape CTP-dependent control in cells would be to infect cells that are not expected to grow, such as neurons. This may account for unexpected body sites of viral development in the present epidemic.
Highlights
Le développement de la pandémie de COVID-19 est exploré dans une myriade d’articles
Using the widely spread C to U change in this genome’s composition as a base line, we identified nodes where the change is shifted from this direction to another one, favouring transversions rather than transitions, reversing the C to U trend towards U to C enrichment or generating blooms with sudden appearance of multiple branches in the evolution tree
The unstable region of Orf7 could promote the synthesis of the very small membrane protein Orf7b, whose function remains unknown to date
Summary
Le développement de la pandémie de COVID-19 est exploré dans une myriade d’articles. Malgré cette abondance, et en raison de notre anthropocentrisme, il est exceptionnel que les études publiées se placent du point de vue du virus. (1) Il s’agit du précurseur immédiat d’un des quatre nucléotides formant le génome du virus ; (2) le CTP est requis pour la synthèse des précurseurs liponucléotidiques de l’enveloppe virale ; (3) les ARN de transfert humains sont synthétisés à partir de 415 gènes ne codant pas leur extrémité CCA 3 OHterminale — cette séquence est synthétisée par une nucléotidyltransférase à partir de CTP [11] ; et pour finir (4) la « décoration » des protéines par des glycosylations compliquées se fait en parallèle avec la traduction dans le réticulum endoplasmique via l’ancrage de substrats par le dolichyl-phosphate, produit par une kinase qui utilise le CTP, et non l’ATP, comme donneur de phosphate [12]. Il s’en suit que les erreurs de réplication accidentelles vont tendre à remplacer la cytosine par l’uracile dans le génome
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