Type VI secretion system effectors as modulators of host immunometabolism: organelle stress, nutritional immunity, and therapeutic opportunities
TL;DR
Viewing the T6SS through an immunometabolic framework may reveal therapeutic vulnerabilities overlooked by conventional models of bacterial toxicity and competition and discuss strategies to define T6SS-driven metabolic fluxes and evaluate host-directed, anti-virulence, and microbiome-engineering approaches.
Abstract
Metabolic reprogramming is a central determinant of host defense and pathogen persistence during infection. Although the bacterial type VI secretion system (T6SS) is primarily recognized as a contact-dependent apparatus for interbacterial competition and effector delivery, emerging evidence indicates that T6SS activity can also influence host metabolism at cellular, nutritional, and microbial-community levels. Here, we organize current evidence into three mechanistic tiers: direct biochemical interference with lipids, metabolites, or metal ions; organelle- and signaling-mediated immunometabolic reprogramming; and indirect metabolic effects arising from T6SS-dependent remodeling of microbial communities. T6SS effectors can disrupt endoplasmic-reticulum lipid homeostasis, activate the unfolded protein response and autophagy, alter mitochondrial Ca2+ handling and dynamics, promote redox imbalance, and modulate metabolically sensitive immune pathways including phosphoinositide 3-kinase (PI3K)-Akt, inflammasome, and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. T6SS-associated proteins also mediate manganese and zinc acquisition or sequestration, linking microbial nutrient acquisition to host nutritional immunity. At the community level, T6SS-mediated competition may reshape resource allocation, horizontal gene transfer, and microbiome-derived metabolite production. However, while T6SS-induced organelle stress is well established, direct causal links to systemic metabolic diseases, including type 2 diabetes and dyslipidemia, remain unproven. We therefore distinguish direct metabolic measurements from inferences based on organelle damage or signaling changes and discuss strategies to define T6SS-driven metabolic fluxes and evaluate host-directed, anti-virulence, and microbiome-engineering approaches. Viewing the T6SS through an immunometabolic framework may reveal therapeutic vulnerabilities overlooked by conventional models of bacterial toxicity and competition.