Regulatory Mechanisms Governing Cell Wall Biogenesis in, and Host Immune Modulation Against, Acinetobacter baumannii

Abstract

The emergence of multidrug-resistant Acinetobacter baumannii presents a critical threat to global health, driven by its capacity to evade antimicrobial therapies and persist in hostile environmental conditions. This dissertation explores the interconnected roles of bacterial zinc (Zn) homeostasis, cell wall biogenesis, and host immune responses, revealing how metal regulation influences both A. baumannii pathogenesis and host defense mechanisms. Central to this investigation are COG0523 family proteins, key mediators of Zn-dependent processes essential for bacterial fitness and virulence. ZigA coordinates Zn homeostasis with cell envelope integrity by interacting with the lytic transglycosylase SltB, linking metal availability to peptidoglycan remodeling. MigC, another COG0523 protein, functions as a Zn-dependent inhibitor of MurD, a critical enzyme in peptidoglycan synthesis. This regulation ensures cell wall integrity and bacterial survival under Zn-limiting conditions, while loss of MigC sensitizes A. baumannii to β-lactam antibiotics, identifying a novel therapeutic vulnerability. On the host side, Zn sequestration emerges as a pivotal factor in immune defense. The Zn-binding protein calprotectin, particularly its S100A9 component, regulates immune homeostasis during A. baumannii infection. S100A9 deficiency appears to disrupt this balance by enhancing ZNRF1 protein degradation activity, potentially reducing the abundance of its targets like Cav1, which may promote immune cell apoptosis, thereby contributing to increased bacterial colonization and tissue damage. Together, these findings elucidate the complex interplay between bacterial metal homeostasis, cell wall dynamics, and host immune regulation. By identifying critical regulatory nodes and potential therapeutic targets, this dissertation establishes a framework for novel strategies to combat multidrug-resistant A. baumannii, contributing to broader efforts in addressing the global challenge of antimicrobial resistance.