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I will extend our published work (Science 2016, Science 2021, Nature Micro 2021, Nature Micro 2022) to describe how bacteria, such as Pseudomonas and Mycobacteria, can evolve from environmental saprophytes into specialist lung pathogens through discrete (and generalisable) steps involving (i) saltational evolution of virulence in specific environmental clones driven by horizontal gene transfer; (ii) allopatric, within-host adaptation during chronic infection; (iii) constrained evolution while transmission is via environmental intermediaries; and eventually (iv) accelerated pathogenic evolution once direct person-to-person transmission is established.
I will discuss how innate immunity may drive host-specific adaptations through transcriptional rewiring and provide targets for host-directed therapy.
