Devaux Christian A, Fantini Jacques
Laboratory Microbes Evolution Phylogeny and Infection (MEPHI), Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.
Centre National de la Recherche Scientifique (CNRS-SNC5039), Marseille, France.
Front Microbiol. 2023 Jul 13;14:1199561. doi: 10.3389/fmicb.2023.1199561. eCollection 2023.
Like other coronaviruses, SARS-CoV-2 has ability to spread through human-to-human transmission and to circulate from humans to animals and from animals to humans. A high frequency of SARS-CoV-2 mutations has been observed in the viruses isolated from both humans and animals, suggesting a genetic fitness under positive selection in both ecological niches. The most documented positive selection force driving SARS-CoV-2 mutations is the host-specific immune response. However, after electrostatic interactions with lipid rafts, the first contact between the virus and host proteins is the viral spike-cellular receptor binding. Therefore, it is likely that the first level of selection pressure impacting viral fitness relates to the virus's affinity for its receptor, the angiotensin I converting enzyme 2 (ACE2). Although sufficiently conserved in a huge number of species to support binding of the viral spike with enough affinity to initiate fusion, ACE2 is highly polymorphic both among species and within a species. Here, we provide evidence suggesting that when the viral spike-ACE2 receptor interaction is not optimal, due to host-switching, mutations can be selected to improve the affinity of the spike for the ACE2 expressed by the new host. Notably, SARS-CoV-2 is mutation-prone in the spike receptor binding domain (RBD), allowing a better fit for ACE2 orthologs in animals. It is possibly that this may also be true for rare human alleles of ACE2 when the virus is spreading to billions of people. In this study, we present evidence that human subjects expressing the rare EG allele of ACE2 with higher allele frequencies in European populations exhibit a improved affinity for the SARS-CoV-2 spike NY variant of the virus. This may suggest that this viral NY variant emerged in the human population after SARS-CoV-2 had infected a human carrying the rare EG allele of ACE2. In addition, this viral evolution could impact viral replication as well as the ability of the adaptive humoral response to control infection with RBD-specific neutralizing antibodies. In a shifting landscape, this ACE2-driven genetic drift of SARS-CoV-2 which we have named the 'boomerang effect', could complicate the challenge of preventing COVID with a SARS-CoV-2 spike-derived vaccine.
与其他冠状病毒一样，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）能够通过人际传播进行扩散，并在人类与动物之间循环传播。在从人类和动物中分离出的病毒中均观察到SARS-CoV-2的高频突变，这表明在两个生态位中，该病毒在正选择下具有遗传适应性。推动SARS-CoV-2突变的最有文献记载的正选择力是宿主特异性免疫反应。然而，在与脂筏发生静电相互作用后，病毒与宿主蛋白的首次接触是病毒刺突蛋白与细胞受体的结合。因此，影响病毒适应性的第一级选择压力很可能与病毒对其受体血管紧张素I转换酶2（ACE2）的亲和力有关。尽管ACE2在大量物种中具有足够的保守性，以支持病毒刺突蛋白以足够的亲和力结合从而启动融合，但ACE2在物种间和物种内都具有高度多态性。在此，我们提供的证据表明，当由于宿主转换导致病毒刺突蛋白与ACE2受体的相互作用不理想时，可以选择突变来提高刺突蛋白对新宿主所表达的ACE2的亲和力。值得注意的是，SARS-CoV-2在刺突受体结合域（RBD）中易于发生突变，从而使其能更好地适应动物体内的ACE2直系同源物。当病毒传播到数十亿人时，对于ACE2的罕见人类等位基因而言，情况可能也是如此。在本研究中，我们提供的证据表明，在欧洲人群中表达罕见EG等位基因且等位基因频率较高的人类受试者，对SARS-CoV-2病毒的NY变异株刺突蛋白表现出更高的亲和力。这可能表明，这种病毒NY变异株是在SARS-CoV-2感染了携带罕见ACE2-EG等位基因的人类之后在人群中出现的。此外，这种病毒进化可能会影响病毒复制以及适应性体液反应通过RBD特异性中和抗体控制感染的能力。在不断变化的情况下，我们将这种由ACE2驱动的SARS-CoV-2基因漂移称为“回旋镖效应”，这可能会使使用源自SARS-CoV-2刺突蛋白的疫苗预防新冠疫情的挑战变得更加复杂。
