Pan Wu, Beibei Fu, Dongqi Nan, Yuan Wen, Hengyu Wang, Ziyuan Zhang, Chenglong Rao, Xiaoxue Lu, Mengru Wang, Yong Sheng, Jingmin Yan, Guangqiang Zhao, Senquan Zheng, Changhao Yao, Kewei Yu, Ling Deng, Xiaoyuan Lin, Xuhu Mao, Zhiqiang Hu, Qian Li
Melioidosis is a life-threatening infectious disease caused by Burkholderia pseudomallei with limited therapeutic options. Multinucleated giant cell (MNGC) formation is known to facilitate B. pseudomallei dissemination and melioidosis progression, yet the underlying mechanism remains unclear. Here, we show that the type VI secretion system effector Hcp1 promotes MNGC formation by targeting host arginase-1 (ARG1). Hcp1 modifies ARG1 at residues 78 and 86, enhances its enzymatic activity, and redirects arginine metabolism toward polyamine biosynthesis. Polyamine accumulation upregulates transcription of endothelial selectin (E-selectin), a cell adhesion molecule required for intercellular fusion. Elevated E-selectin in turn promotes MNGC assembly and accelerates B. pseudomallei dissemination. Pharmacological ARG1 inhibition or siRNA-mediated Sele knockdown confers significant protection against B. pseudomallei infection in murine models. These findings identify a host-directed mechanism by which Hcp1 drives bacterial dissemination and establish the Hcp1-ARG1-E-selectin axis as a potential host-directed therapeutic target.