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 also enables us to address two long-standing and interrelated questions in emerging pathogen research, regarding the influence of transmission bottleneck size on emergence probability and the importance of "pre-adapted" mutations circulating in the animal reservoir [17, 71, [76] [77] [78] 95] . In both cases, the answer depends on the cross-scale reproductive number α of a mutant virion that governs the frequency feedback. Under most circumstances, wider bottlenecks boost the probability of emergence (Fig 4A,B) , because they favor the onward transmission of mutant virions when they are rare; this is particularly vital for the first transmission of mutant virions (i.e. Step 3 in Fig. 5 ). The exception is for long-term infections with α < 1, such that the mutant tends to decline in frequency in the infected host population. Under these circumstances, wider bottlenecks hinder emergence by propagating reductions in the frequency of the mutant strain more efficiently from host to host (Step 4 in Fig. 5 ). Conventional thinking about the influence of bottlenecks on viral adaptation emphasizes fitness losses due to genetic drift and the effects of Muller's ratchet [35-37, 39, 40] , which become more severe for narrower bottlenecks. Contrary to these negative effects of narrow bottlenecks, our findings highlight that narrower bottlenecks can aid emergence in long-term infections with a cross-scale conflict in selection (Fig 4B) . Here the adaptive gain in transmissibility at population scales can be impeded by the selective disadvantage at the within-host scale, but, intriguingly, this disadvantage is neutralized by genetic drift arising from narrow bottlenecks. Given the evidence for cross-scale evolutionary conflicts for HIV-1 [58, 63, 64, 96] , our results suggest the possibility that HIV-1's narrow transmission bottleneck [44] could play a role in the emergence of novel strains (e.g. drug resistant strains).