The danger hypothesis of virulence evolution

Multicellular organisms regularly encounter microbes, which are, however, only rarely pathogenic. Our understanding of this phenomenon is currently restricted due to lacking theory on evolutionary transitions between non-pathogenic and pathogenic microbial lifestyles. Here we addressed this gap by investigating a mathematical model of host-microbe interactions that is based on the danger theory of immunology, which states that danger signals related to host tissue damage play a key role in activating immune responses. We formally implemented this idea by assuming that immune activation increases with costs that microbes cause to their host, and we compared this to scenarios in which immune activation depends only on the presence or load of infecting microbes. Our model analysis revealed that cost-based - but not presence or load-based - immune activation favours the evolution of avirulence and associated non-pathogenic microbial lifestyles. Based on our results, we propose the danger hypothesis of virulence evolution which states that evolution towards avirulence and intermediate virulence are both possible - depending on whether hosts can accurately assess costs generated by microbes. The idea that basic host immune responses can select for avirulence offers a new explanation for why most microbes are not pathogenic to a given host.