Abstract

Acinetobacter baumannii is a formidable nosocomial pathogen whose multidrug resistance and immune evasion capabilities present a major therapeutic challenge. This study identifies the type VI secretion system (T6SS) effector VgrG2 as a critical virulence regulator in A. baumannii . VgrG2 employs a two-pronged strategy to undermine host innate immunity. First, it transcriptionally represses the major adhesin Csu pilus, reducing bacterial recognition, phagocytic uptake, and neutrophils recruitment. Second, VgrG2 directly targets and hyperactivates the small GTPase Rac1 within phagocytes. This leads to actin cytoskeletal disarray, which drives excessive macropinocytosis, resulting in compromised phagocytosis and methuosis—a non-apoptotic, vacuole-dependent death specific to phagocytes. Thus, VgrG2 selectively eliminates key immune sentinels and alters pulmonary inflammation, promoting bacterial persistence and dissemination. These findings extend the role of T6SS effectors beyond interbacterial competition to include sophisticated eukaryotic-directed attacks, and highlight the VgrG2-Rac1 axis as a promising therapeutic target.