PIrates of the Vacuole: Phosphoinositide Hijacking by T4SS Intracellular Pathogens

Abstract Intracellular bacteria equipped with a Type IV Secretion Systems (T4SS), including Legionella pneumophila, Coxiella burnetii, Brucella abortus, and Anaplasma/Ehrlichia species, evolved a convergent strategy of exploiting host cell lipids at every stage of infection, from cholesterol-rich raft-mediated entry to the establishment of replicative vacuoles that evade lysosomal destruction. Indeed, these pathogens actively remodel host cell membranes by deploying T4SS effectors that bind, generate, or deplete specific lipid species, in particular phosphoinositides and cholesterol, to dictate the identity and trafficking fate of their containing vacuole. A remarkable diversity of effectors with lipid-binding or lipid-modifying activities has now been characterised across these pathogens: from the PI4P-centric Dot/Icm effector cascade of Legionella to the cooperating CvpB, CvpE, and Vice triad of Coxiella, and the phosphoinositide-binding immune evasion effector BtpA of Brucella. These pathogens also tap into host lipid droplets for energy and membrane precursors, modulate bioactive lipid mediators such as prostaglandins to curb immune clearance, and present atypical surface lipids to minimise pattern recognition. Advances in lipidomics, including a landmark systematic identification of novel α-helical PI-binding effector folds conserved across Legionella and Coxiella, have shed new light on these processes with unprecedented resolution. This review examines the shared and divergent lipid-subversion strategies of T4SS-bearing intracellular pathogens from an integrated molecular, cellular, and lipidomic perspective, and highlights emerging opportunities for host-directed therapeutic intervention.