Hydrogen cyanide generation by <i>Pseudomonas aeruginosa</i> blunts the host innate immune response

BACKGROUND: The biological mediator hydrogen cyanide (HCN) is produced by certain pathogenic bacteria. HCN exerts multiple effects in mammalian cells: at low concentrations it has cytoprotective regulatory effects, whereas at high concentrations it blocks mitochondrial electron transport by inhibiting cytochrome c oxidase, thereby halting cellular metabolism. Here, we evaluated whether bacterial HCN confers resistance to the host immune response. We used Pseudomonas aeruginosa as a model organism, since it is a clinically significant HCN-generating bacterial species and a common cause of nosocomial infections. METHODS: The study used bacterial mutants, macrophage co-cultures, cyanide quantification, phagocytosis and bioenergetics assays, and mouse infection models to assess HCN's role in immune evasion. RESULTS: Compared to wild type P. aeruginosa, genetically HCN-deficient bacteria were more susceptible to killing by immune cells in vitro and were cleared more rapidly in mouse models of systemic infection. Increased leukocyte killing was not due to increased phagocytosis. Pharmacological scavenging of HCN (by vitamin B12 or trihistidyl cobinamide) also enhanced leukocyte bacterial killing. CONCLUSIONS: These findings support the concept that HCN acts as a bacterial defense mechanism against the host's immune response. Targeting bacterial HCN (through inhibition of its biogenesis or by scavenging) could be a potential therapeutic strategy to improve the immune clearance of P. aeruginosa infections.