| Summary: | <i>Yersinia pestis</i>, the causative agent of plague, has a complex infectious cycle that alternates between mammalian hosts (rodents and humans) and insect vectors (fleas). Consequently, it must adapt to a wide range of host environments to achieve successful propagation. <i>Y. pestis</i> PhoP is a response regulator of the PhoP/PhoQ two-component signal transduction system that plays a critical role in the pathogen’s adaptation to hostile conditions. PhoP is activated in response to various host-associated stress signals detected by the sensor kinase PhoQ and mediates changes in global gene expression profiles that lead to cellular responses. <i>Y. pestis</i> PhoP is required for resistance to antimicrobial peptides, as well as growth under low Mg<sup>2+</sup> and other stress conditions, and controls a number of metabolic pathways, including an alternate carbon catabolism. Loss of <i>phoP</i> function in <i>Y. pestis</i> causes severe defects in survival inside mammalian macrophages and neutrophils in vitro, and a mild attenuation in murine plague models in vivo, suggesting its role in pathogenesis. A <i>Y. pestis</i><i>phoP</i> mutant also exhibits reduced ability to form biofilm and to block fleas in vivo, indicating that the gene is also important for establishing a transmissible infection in this vector. Additionally, <i>phoP</i> promotes the survival of <i>Y. pestis</i> inside the soil-dwelling amoeba <i>Acanthamoeba castellanii</i>, a potential reservoir while the pathogen is quiescent. In this review, we summarize our current knowledge on the mechanisms of PhoP-mediated gene regulation in <i>Y. pestis</i> and examine the significance of the roles played by the PhoP regulon at each stage of the <i>Y. pestis</i> life cycle.
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