The Genetic Basis of <i>Escherichia coli</i> Pathoadaptation to Macrophages

<div><p>Antagonistic interactions are likely important driving forces of the evolutionary process underlying bacterial genome complexity and diversity. We hypothesized that the ability of evolved bacteria to escape specific components of host innate immunity, such as phagocytosis and killing by macrophages (MΦ), is a critical trait relevant in the acquisition of bacterial virulence. Here, we used a combination of experimental evolution, phenotypic characterization, genome sequencing and mathematical modeling to address how fast, and through how many adaptive steps, a commensal <i>Escherichia coli</i> (<i>E. coli</i>) acquire this virulence trait. We show that when maintained <i>in vitro</i> under the selective pressure of host MΦ commensal <i>E. coli</i> can evolve, in less than 500 generations, virulent clones that escape phagocytosis and MΦ killing <i>in vitro</i>, while increasing their pathogenicity <i>in vivo</i>, as assessed in mice. This pathoadaptive process is driven by a mechanism involving the insertion of a single transposable element into the promoter region of the <i>E. coli yrfF</i> gene. Moreover, transposition of the IS186 element into the promoter of <i>Lon</i> gene, encoding an ATP-dependent serine protease, is likely to accelerate this pathoadaptive process. Competition between clones carrying distinct beneficial mutations dominates the dynamics of the pathoadaptive process, as suggested from a mathematical model, which reproduces the observed experimental dynamics of <i>E. coli</i> evolution towards virulence. In conclusion, we reveal a molecular mechanism explaining how a specific component of host innate immunity can modulate microbial evolution towards pathogenicity.</p>