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Pulmonary ketogenesis promotes tolerance to bacterial infection

ABSTRACT: Tolerance is a major defense strategy against infection. During the host response to pathogens, tolerance restricts inflammatory damage to tissues, maintaining the long-term integrity of organs. The mechanisms that establish tolerance are poorly understood. We analyzed pulmonary isolates of Pseudomonas aeruginosa that evolved to coexist with tolerant hosts and found that these opportunistic pathogens facilitate tolerance by stimulating ketogenesis. Ketone body production in the airway limits the accumulation of detrimental factors that injure the lung, such as inflammatory cytokines and effector phagocytes. Although ketones are typically synthesized in the liver, in situ metabolo-transcriptomic studies revealed that P. aeruginosa drives their generation in the lung by co-opting the metabolism of alveolar macrophages, which are pulmonary cells of hepatic origin. This phenomenon was restricted to clinical isolates and not observed with laboratory strains of P. aeruginosa , confirming the unique metabolo-tolerogenic properties of ESKAPE pathogens adapted to the human lung.

ORGANISM(S): Mus musculus

PROVIDER: GSE203352 | GEO | 2023/10/12

REPOSITORIES: GEO

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