Inside Enemy Lines: Adhesion, Invasion, and Intracellular Persistence of Acinetobacter baumannii in the Respiratory Epithelium

<i>Acinetobacter baumannii</i> is a critical pathogen and a leading cause of hospital-acquired pneumonia, especially in immunocompromised patients. Although most research has focused on antimicrobial resistance, growing evidence shows that <i>A. baumannii</i> can efficiently adhere to, invade, and persist within human airway epithelial cells. Thus, the aim of this review is to summarize current knowledge on the mechanisms used by <i>A. baumannii</i> to establish infection, highlighting the bacterial traits responsible for attachment to airway epithelia, entry into host cells, manipulation of intracellular trafficking pathways to avoid degradation, metabolic adaptation to the host environment, and interference with immune defenses. The findings reported herein come from host-pathogen studies performed using epithelial cell lines, <i>Galleria mellonella</i>, and murine models, and from human primary airway cells. Despite the prominent role of the outer membrane protein OmpA, it is clear that <i>A. baumannii</i> pathogenicity relies on multiple, often redundant, virulence strategies to secure its intracellular niche and resist host pressures. Remarkably, strain heterogeneity in virulence traits between lab-domesticated and clinical isolates supports differential intracellular behavior and pathogenic potential. A deeper understanding of <i>A. baumannii</i> infection mechanisms is essential to design anti-virulence strategies that disarm this life-threatening bacterium, reduce selective pressure, limit resistance, and guide next-generation therapeutic interventions.