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

Our cross-scale analysis identifies the mechanistic counterpart to this phenomenological "mutation rate", which is the probability that an individual infected initially with the wild-type strain ends up transmitting at least one virion of the mutant strain (Step 3 in Fig 5) . This quantity, which is approximated by the black contours in Fig 2, is governed chiefly by the ability of the mutant strain to reach an appreciable frequency within the host over the course of an infection. This is evident from the strong dependence on the strength of within-host selection-which surprisingly is much stronger than the dependence on the transmission advantage of mutant virions-and the higher values found for larger bottleneck widths, which favor transmission of low-frequency mutants through a straight-forward sampling effect. This sampling effect is consistent with the theoretical work of Geoghegan et al. [17] , and the experimental study of Frise et al. [42] , who found larger bottlenecks increased the likelihood of mutant viral strains being transmitted between hosts. The duration of infection plays a crucial role, and our analysis showed that achieving this first transmission of the adaptive mutant is a key barrier to evolutionary emergence for short-term infections (Fig 2A,B) . This finding aligns with the recent observation that putative immune-escape mutants of pandemic H1N1 influenza, which should have a within-host fitness advantage, were generated readily in infected humans but did not reach high within-host frequency and have been detected very rarely at the consensus level All rights reserved. No reuse allowed without permission.