Legionella pneumophila, a Rosetta stone to understanding bacterial pathogenesis

Legionella pneumophila is an environmentally acquired pathogen that causes respiratory disease in humans. While the discovery of L. pneumophila is relatively recent compared to other bacterial pathogens, over the past 50 years, L. pneumophila has emerged as a powerhouse for studying host-pathogen interactions. In its natural habitat of fresh water, L. pneumophila interacts with a diverse array of protozoan hosts and readily evolve to expand their host range. This has led to the accumulation of the most extensive arsenal of secreted virulence factors described for a bacterial pathogen and their ability to infect humans. Within amoebae and human alveolar macrophages, the bacteria replicate within specialized membrane-bound compartments, establishing L. pneumophila as a model for studying intracellular vacuolar pathogens. In contrast, the virulence factors required for intracellular replication are specifically tailored to individual host cells types, allowing the pathogen to adapt to variation between disparate niches. The broad host range of this pathogen, combined with the extensive diversity and genome plasticity across the Legionella genus, has thus established this bacterium as an archetype to interrogate pathogen evolution, functional genomics, and ecology. In this review, we highlight the features of Legionella that establish them as a versatile model organism, new paradigms in bacteriology and bacterial pathogenesis resulting from the study of Legionella, as well as current and future questions that will undoubtedly expand our understanding of the complex and intricate biology of the microbial world.