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Complex reprogramming of Yersinia virulence factor expression during infection

Yersinia pseudotuberculosis evolved numerous strategies to survive in mammalian hosts. A hallmark is the ability to rapidly adjust the lifestyle upon host entry to prevent attacks by the host immune systems. One important strategy is that Y. pseudotuberculosis uses a type III secretion system to apply toxic effector proteins into professional phagocytes to prevent phagocytosis. Some isolates also produce the cytotoxic necrotizing factor (CNFY), which enhances Yop translocation, contributes significantly to the induction of acute inflammatory responses and results in extensive tissue destruction. Presence of CNFY leads to a strong reduction of professional phagocytes and natural killer cells, whereas a loss of the toxin allows efficient tissue infiltration of these immune cells and rapid killing of the pathogen. A suppression of CNFY function, however, increases interferon-γ-mediated responses, comprising non-inflammatory antimicrobial activities and tolerogenesis. This process is accompanied by a preterm reprogramming of the pathogen's transcriptional response towards persistence, which gives the bacteria a fitness edge against host responses and facilitates establishment of a commensal-type life-style without disease symptoms. To capture the range, magnitude and complexity of the underlying control mechanisms, we used different RNA-seq-based approaches to identify control factors important for this process. We identified a range of complex regulatory cascades implicating sensory and regulatory RNAs. In summary, our findings highlight a novel level of complexity in which the concerted action of transcriptional regulators and non-coding RNAs adjusts the control of Yersinia fitness and virulence to the requirements of their virulent lifestyle.