Plagued by the Past, Pressed by the Present: A One Health Perspective on Yersinia pestis

<i>Yersinia pestis</i>, the causative agent of plague, is arguably the most devastating pathogen in human history. Paleogenomic studies indicate its presence as early as the Neolithic era. It evolved from <i>Yersinia pseudotuberculosis</i>, with divergence estimates ranging from 1500 to 20,000 years ago, most often placed around 5000 years ago. Its natural reservoirs are wild mammals, particularly rodents, with fleas serving as vectors, while humans are incidental hosts. Over time, <i>Y. pestis</i> has acquired multiple virulence factors that disrupt immune responses and can lead to rapid, often fatal disease. Because the bacterium is maintained in wildlife cycles and can spill over to domestic animals, eradication is difficult, if not impossible. Nevertheless, mitigation is achievable using a One Health approach integrating human health, animal health, and the health of the environment. Neither vaccines nor monoclonal antibodies are currently licensed in most Western countries, thus, antibiotics remain the mainstay of therapy. Timely administration, ideally within 24 h of symptom onset, is critical, particularly in pneumonic forms. Phage therapy is under investigation as a potential treatment. Though often neglected in high-income settings, plague remains endemic in several regions, with the highest burden reported in Madagascar and the Democratic Republic of the Congo.