The IrlS2-IrlR2 two-component system is a global regulator of biofilm formation, stress adaptation, and virulence in <i>Burkholderia pseudomallei</i>

<i>Burkholderia pseudomallei</i>, which causes melioidosis, poses a serious threat to human and animal health in tropical and subtropical regions worldwide. Classified as a tier 1 biothreat agent by the U.S. CDC and a category II pathogen in China, <i>B. pseudomallei</i> causes severe pneumonia and septicemia with case-fatality rates approaching 50%. Despite its medical and epidemiological significance, the regulatory mechanisms controlling its virulence and environmental persistence remain poorly understood. This study identifies IrlS2-IrlR2 as a previously uncharacterized two-component system (TCS) that acts as a global regulator integrating biofilm formation, stress adaptation, and virulence. Functional and transcriptomic analyses reveal that IrlS2-IrlR2 modulates secretion systems, iron homeostasis, and redox balance. These findings deepen our understanding of <i>B. pseudomallei</i> pathogenesis and highlight the role of TCS-mediated regulatory networks.