<i>Brucella</i> spp. – Emerging Insights Into Virulence Strategies: T4SS, CβG, Intracellular Replication, and Beyond

Brucellosis, caused by Brucella species, is a major zoonotic disease with substantial public health and veterinary impact worldwide. This review provides an integrated overview of key virulence mechanisms employed by Brucella, with emphasis on the VirB Type IV secretion system (T4SS), cyclic β-1,2-glucans (CβG), lipopolysaccharide (LPS) and the bacterium's intracellular replication cycle. These factors enable the pathogen to evade host immune recognition, remodel intracellular compartments, and maintain long-term survival in diverse tissues. Building on recent advances, we propose a functional hierarchy of VirB T4SS effectors that distinguishes core components required for intracellular persistence from context-dependent effectors that modulate tissue specificity and disease severity. By linking VirB T4SS activity with CβG-driven alterations of phagosomal trafficking and LPS-mediated dampening of Toll-like receptor 4 signaling, we outline a multilayered model of immune escape and chronic infection. On this basis, we identify non-redundant T4SS effectors, CβG biosynthetic enzymes and defined LPS modifications as priority candidates for the development of targeted diagnostics, host-directed or anti-virulence therapies, and next-generation vaccines against brucellosis.