Cross-scale dynamics and the evolutionary emergence of infectious diseases

Sebastian J. Schreiber; Ruian Ke; Claude Loverdo; Miran Park; Priyanna Ahsan; James O. Lloyd-Smith

While there are not sufficient data from past emergence events to test our model's conclusions, recent studies combining animal transmission experiments with deep sequencing have exhibited many phenomena aligned with our findings. Moncla et al. [43] conducted deep sequencing analyses of H1N1 influenza viruses, in the context of ferret airborne transmission experiments that examined the adaptation of avian-like viruses to the mammalian host. Their results provide in-depth insights into selection within hosts and at transmission bottlenecks, for a range of mutations on genetic backgrounds that change as adaptation proceeds (i.e. equivalent to numerous separate implementations of our model of a single mutational step). They observe a fascinating range of dynamics: some mutations appeared to have α moderately above 1, exhibiting modest increases in frequency between generations, but achieved this outcome with different traits (e.g. S113N on the HA190D225D background exhibited strong within-host selection and no evident transmission advantage, while D265V showed weak within-host selection but its frequency rises in transmission). Another mutation (I187T on the 'Mut' background) appeared to have α 1 and exhibited strong selection at both scales; notably, this mutation is widespread in 17/17 human-derived isolates of the post-emergence 1918 virus, consistent with the successful and rapid emergence our model would predict. Moncla et al. also present substantial evidence of cross-scale conflict in selection, as one mutation (G225D on 'Mut' background) exhibited declining frequencies within ferrets but rose to fixation in 2/2 transmission events, while numerous mutations in the HA2 region rose in frequency within the host but were eliminated in transmission. Another study examined a set of 'gain-of-function' mutations in H5N1 influenza in ferrets, and reported a slow rise in frequency when the virus was passaged between ferrets by intranasal inoculation, then rapid fixation of these mutations during airborne transmission [24] ; the airborne transmission data are consistent with strong between-host selection and a high α value (though we emphasize that circulating H5N1 viruses required substantial modification to the favorable genetic background used in those experiments). Intriguingly, Moncla et al. synthesized their results with those of earlier studies [41, 49, 62] to hypothesize that the 'stringency' of the transmission bottleneck varies systematically during the course of viral adaptation, with loose bottlenecks prevailing when viruses first encounter a new host species (and perhaps again when the virus is host-adapted), and much tighter bottlenecks at the key juncture in host adaptation when a genotype with greater transmissibility is available to be selected. If this hypothesis is correct, then our findings can be applied to each adaptive step independently, and may help to identify which viral traits are most crucial to adaptive steps subject to tighter or looser bottlenecks.