Competitive exclusion strengthens selection for transmissibility and increases the benefit of recombination for within-host adaptation.

Abstract Pathogens experience selection at multiple scales, given the need to transmit between hosts and replicate within them. This presents the challenge of cross-scale selective conflict when adaptations to one scale compromise fitness at another, such as mutations that improve transmissibility but make individuals less competitive within hosts. Selection operates differently at these scales, with tight transmission bottlenecks subjecting pathogen populations to genetic drift, and large population sizes within hosts enabling efficient selection for beneficial mutations. Compounding the reduction in diversity by transmission bottlenecks is the occupant-intruder competitive strategy exhibited by some pathogens, where the first variant to colonize a host prevents later arriving variants from contributing to infection, preventing immigration and turning transmission into a “founder takes all” contest. Here, we used multiple modeling approaches to examine how this behavior affects the efficiency of selection for both transmissibility and within- host fitness. We find that in the face of a trade-off, selection for transmissibility is maximized under a tight transmission bottleneck that minimizes within-host competition during colonization. While mutations with increased within-host fitness are favored during within-host replication, an occupant-intruder strategy prevents these mutants from displacing established residents and propagating across the host population, leading to their extinction if they are insufficiently transmissible. Finally, a model of competition on the scale of the host population revealed that competitive exclusion limits the propagation of mutations with improved within-host fitness, unless resident populations can incorporate alleles from intruding variants by recombination. Thus, competitive exclusion may facilitate the improvement and maintenance of pathogen transmissibility, with directional recombination allowing resident populations to mitigate the potential loss of within-host fitness imposed by this occupant-intruder strategy. Author Summary Transmission is a defining feature of infectious diseases, and so a better understanding of how transmissibility evolves is important for improving disease surveillance and prevention. Successful transmission is often achieved by a small number of individuals which, after establishing residency in a host, may prevent newcomers from participating in infection. Here, we use modeling to examine how competitive exclusion of challengers by resident populations affects the balance between within-host competitive ability and transmissibility. We find that competitive exclusion strengthens selection for transmissibility by disproportionately benefitting the first variant to colonize a host and preventing mutants that may be more competitive but less transmissible from displacing established residents. Competitive exclusion also limits the propagation of mutants that improve within-host fitness without reducing transmissibility, however, increasing the advantage of recombination that allows resident populations to acquire beneficial alleles from challengers. Competitive strategies that allow pathogens to “claim ownership” of hosts may thus help pathogen populations maintain transmissibility, with genetic recombination facilitating within-host adaptation through the incorporation of beneficial alleles from challengers.