Pseudomonas aeruginosa Effector ExoS Inhibits ROS Production in Human Neutrophils

• Published in: Cell host & microbe Vol. 21; no. 5; pp. 611 - 618.e5
• Main Authors: Vareechon, Chairut, Zmina, Stephanie Elizabeth, Karmakar, Mausita, Pearlman, Eric, Rietsch, Arne
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10-05-2017
• Subjects: ADP Ribose Transferases - antagonists & inhibitors; ADP Ribose Transferases - metabolism; ADP-Ribosylation - drug effects; Animals; Bacterial Toxins - antagonists & inhibitors; Bacterial Toxins - immunology; Colony Count, Microbial; effector function; Epithelium - pathology; Eye - pathology; Female; GTPase-Activating Proteins - antagonists & inhibitors; Humans; Immunity, Innate; keratitis; Mice, Inbred C57BL; NADPH Oxidases - metabolism; Neutrophils - enzymology; Neutrophils - immunology; Neutrophils - metabolism; Phagocytosis; Phosphatidylinositol 3-Kinases - metabolism; Pseudomonas aeruginosa - immunology; Pseudomonas aeruginosa - metabolism; Pseudomonas aeruginosa - pathogenicity; Pseudomonas Infections - immunology; Pseudomonas Infections - microbiology; ras Proteins - drug effects; ras Proteins - metabolism; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Survival Analysis; T3SS; type III secretion; Type III Secretion Systems - drug effects; effector function; keratitis; T3SS; type III secretion
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2017.04.001

Neutrophils are the first line of defense against bacterial infections, and the generation of reactive oxygen species is a key part of their arsenal. Pathogens use detoxification systems to avoid the bactericidal effects of reactive oxygen species. Here we demonstrate that the Gram-negative pathogen Pseudomonas aeruginosa is susceptible to reactive oxygen species but actively blocks the reactive oxygen species burst using two type III secreted effector proteins, ExoS and ExoT. ExoS ADP-ribosylates Ras and prevents it from interacting with and activating phosphoinositol-3-kinase (PI3K), which is required to stimulate the phagocytic NADPH-oxidase that generates reactive oxygen species. ExoT also affects PI3K signaling via its ADP-ribosyltransferase activity but does not act directly on Ras. A non-ribosylatable version of Ras restores reactive oxygen species production and results in increased bacterial killing. These findings demonstrate that subversion of the host innate immune response requires ExoS-mediated ADP-ribosylation of Ras in neutrophils.
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•P. aeruginosa inhibits ROS production by neutrophils•Inhibition depends on the ADP-ribosyltransferase activities of ExoS and ExoT•ExoS blocks ROS production by ADP-ribosylating Ras on Arg41•ADP-ribosylation of Ras blocks interaction with PI3K
Reactive oxygen species (ROS) production by neutrophils is a key antimicrobial defense. Vareechon et al. show that two type III secreted effectors of Pseudomonas aeruginosa, ExoS and ExoT, independently block ROS production by neutrophils. ExoS ADP-ribosylates Ras, which prevents binding to PI3K, thereby blocking NADPH oxidase activation and ROS production.