A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant

Proceedings of the National Academy of Sciences of the United States of America
Jonathan P AllenAlan R Hauser

Abstract

Emerging evidence suggests the Pseudomonas aeruginosa accessory genome is enriched with uncharacterized virulence genes. Identification and characterization of such genes may reveal novel pathogenic mechanisms used by particularly virulent isolates. Here, we utilized a mouse bacteremia model to quantify the virulence of 100 individual P. aeruginosa bloodstream isolates and performed whole-genome sequencing to identify accessory genomic elements correlated with increased bacterial virulence. From this work, we identified a specific contact-dependent growth inhibition (CDI) system enriched among highly virulent P. aeruginosa isolates. CDI systems contain a large exoprotein (CdiA) with a C-terminal toxin (CT) domain that can vary between different isolates within a species. Prior work has revealed that delivery of a CdiA-CT domain upon direct cell-to-cell contact can inhibit replication of a susceptible target bacterium. Aside from mediating interbacterial competition, we observed our virulence-associated CdiA-CT domain to promote toxicity against mammalian cells in culture and lethality during mouse bacteremia. Structural and functional studies revealed this CdiA-CT domain to have in vitro tRNase activity, and mutations that abro...Continue Reading

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Citations

Aug 28, 2020·Frontiers in Microbiology·Renatas KrasauskasEdita Sužiedėlienė
Oct 31, 2020·International Journal of Molecular Sciences·Larisa N IkryannikovaAndrey A Zamyatnin
Apr 27, 2021·Current Opinion in Structural Biology·Jérémy Guérin, Susan K Buchanan
Sep 26, 2021·Proteins·Leila T AlexanderTorsten Schwede

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