As hosts acquire resistance to viruses, viruses must overcome that resistance to re-establish infectivity, or go extinct. Despite the significant hurdles associated with adapting to a resistant host, viruses are evolutionarily successful and maintain stable coevolutionary relationships with their hosts. To investigate the factors underlying how pathogens adapt to their hosts, we performed a deep mutational scan of the region of the λ tail fiber tip protein that mediates contact with the receptor on λ’s host, Escherichia coli. Phages harboring amino acid substitutions were subjected to selection for infectivity on wild type E. coli, revealing a highly restrictive fitness landscape, in which most substitutions completely abrogate function. A subset of positions that are tolerant of mutation in this assay, but diverse over evolutionary time, are associated with host range expansion. Imposing selection for phage infectivity on three λ-resistant hosts, each harboring a different missense mutation in the λ receptor, reveals hundreds of adaptive variants in λ. We distinguish λ variants that confer promiscuity, a general ability to overcome host resistance, from those that drive host-specific infectivity. Both processes may be important in driving adaptation to a novel host.

随着宿主获得对病毒的抵抗力，病毒必须克服这种抵抗力才能重新建立传染性，否则就会灭绝。尽管适应抗性宿主存在重大障碍，但病毒在进化上是成功的，并与宿主保持稳定的共同进化关系。为了研究病原体如何适应其宿主的潜在因素，我们对 λ 尾纤维尖端蛋白区域进行了深度突变扫描，该区域介导与 λ 宿主大肠杆菌上的受体接触。对具有氨基酸取代的噬菌体进行选择以对野生型大肠杆菌的感染性，揭示了一个高度限制性的健身景观，其中大多数替换完全废除了功能。在该测定中耐受突变但随着进化时间而变化的位置子集与宿主范围扩展有关。对三个抗 λ 宿主进行噬菌体感染性选择，每个宿主在 λ 受体中都具有不同的错义突变，揭示了 λ 中的数百个适应性变体。我们将赋予混杂性（一种克服宿主抗性的一般能力）的 λ 变体与驱动宿主特异性感染性的 λ 变体区分开来。这两个过程对于推动适应新宿主可能很重要。