Reprogramming of <i>Yersinia</i> from Virulent to Persistent Mode Revealed by Complex <i>In Vivo</i> RNA-seq Analysis

<div><p>We recently found that <i>Yersinia pseudotuberculosis</i> can be used as a model of persistent bacterial infections. We performed <i>in vivo</i> RNA-seq of bacteria in small cecal tissue biopsies at early and persistent stages of infection to determine strategies associated with persistence. Comprehensive analysis of mixed RNA populations from infected tissues revealed that <i>Y. pseudotuberculosis</i> undergoes transcriptional reprogramming with drastic down-regulation of T3SS virulence genes during persistence when the pathogen resides within the cecum. At the persistent stage, the expression pattern in many respects resembles the pattern seen <i>in vitro</i> at 26oC, with for example, up-regulation of flagellar genes and <i>invA</i>. These findings are expected to have impact on future rationales to identify suitable bacterial targets for new antibiotics. Other genes that are up-regulated during persistence are genes involved in anaerobiosis, chemotaxis, and protection against oxidative and acidic stress, which indicates the influence of different environmental cues. We found that the Crp/CsrA/RovA regulatory cascades influence the pattern of bacterial gene expression during persistence. Furthermore, <i>arcA</i>, <i>fnr</i>, <i>frdA</i>, and <i>wrbA</i> play critical roles in persistence. Our findings suggest a model for the life cycle of this enteropathogen with reprogramming from a virulent to an adapted phenotype capable of persisting and spreading by fecal shedding.</p>