Highlights d P. aeruginosa-infected macrophages produce itaconate d Itaconate generates membrane stress in P. aeruginosa d Itaconate leads to decreased LPS, but increased EPS, to promote biofilm formation d The EPS-itaconate axis thwarts immune clearance enabling chronic infection

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor best known for regulating cell proliferation and metabolism. PTEN forms a complex with the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) at the plasma membrane, and this complex is known to be functionally impaired in CF. Here, we demonstrated that the combined effect of PTEN and CFTR dysfunction stimulates mitochondrial activity, resulting in excessive release of succinate and reactive oxygen species. This environment promoted the colonization of the airway by Pseudomonas aeruginosa, bacteria that preferentially metabolize succinate, and stimulated an anti-inflammatory host response dominated by immune-responsive gene 1 (IRG1) and itaconate. The recruitment of myeloid cells induced by these strains was inefficient in clearing the infection and increased numbers of phagocytes accumulated under CFTR-PTEN axis dysfunction. This central metabolic defect in mitochondrial function due to impaired PTEN activity contributes to P. aeruginosa infection in CF.

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Acetylation is a broadly conserved mechanism of covalently modifying the proteome to precisely control protein activity. In bacteria, central metabolic enzymes and regulatory proteins, including those involved in virulence, can be targeted for acetylation. In this study, we directly link a putative acetylation system to metabolite-dependent virulence in the pathogen We demonstrate that the and genes, which encode homologs of a deacetylase and an acetyltransferase, respectively, modulate metabolism of acetate, a bacterially derived short-chain fatty acid with important physiological roles in a diversity of host organisms. In , a model arthropod host for infection, the pathogen consumes acetate within the gastrointestinal tract, which contributes to fly mortality. We show that deletion of impairs growth on acetate minimal medium, delays the consumption of acetate from rich medium, and reduces virulence of toward These impacts can be reversed by complementing or by introducing a deletion of into the Δ background. We further show that controls the accumulation of triglycerides in the midgut, which suggests that directly modulates metabolite levels In K-12, is upregulated by cAMP-cAMP receptor protein (CRP), and we identified a similar pattern of regulation in , arguing that the system is activated in response to similar environmental cues. In summary, we demonstrate that proteins likely involved in acetylation can modulate the outcome of infection by regulating metabolite exchange between pathogens and their colonized hosts. The bacterium causes severe disease in humans, and strains can persist in the environment in association with a wide diversity of host species. By investigating the molecular mechanisms that underlie these interactions, we can better understand constraints affecting the ecology and evolution of this global pathogen. The model of infection has revealed that bacterial regulation of acetate and other small metabolites from within the fly gastrointestinal tract is crucial for its virulence. Here, we demonstrate that genes that may modify the proteome of affect virulence toward , most likely by modulating central metabolic pathways that control the consumption of acetate as well as other small molecules. These findings further highlight the many layers of regulation that tune bacterial metabolism to alter the trajectory of interactions between bacteria and their hosts.

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