Abstract
Drug resistance is a growing problem that necessitates new strategies to combat pathogens. Neutrophil phagocytosis and production of intracellular ROS, in particular, has been shown to cooperate with antibiotics in the killing of microbes. This study tested the hypothesis that p85α, the regulatory subunit of PI3K, regulates production of intracellular ROS. Genetic knockout of p85α in mice caused decreased expression of catalytic subunits p110α, p110β, and p110δ, but did not change expression levels of the NADPH oxidase complex subunits p67phox, p47phox, and p40phox. When p85α, p55α, and p50α (all encoded by Pik3r1) were deleted, there was an increase in intracellular ROS with no change in phagocytosis in response to both Fcγ receptor and complement receptor stimulation. Furthermore, the increased intracellular ROS correlated with significantly improved neutrophil killing of both methicillin-susceptible and methicillin-resistant S. aureus. Our findings suggest inhibition of p85α as novel approach to improving the clearance of resistant pathogens.
Highlights
Staphylococcus aureus make up a large proportion of human infections worldwide, causing various diseases that range from acute skin infections to life-threatening systemic toxic shock syndromes
Our work provides a novel target in the regulation of enhancing neutrophil intracellular reactive oxygen species (ROS), which has been shown to cooperate with anti-microbial agents to increase bacterial killing [22, 23]
Consistent with previous studies reporting increased phosphoinositide 3-kinase (PI3K) catalytic subunit degradation upon loss of the stabilizing regulatory subunits [24, 26], p110α, p110β, and p110δ protein expression was substantially reduced in the Pik3r1-/- neutrophils (Figure 1C)
Summary
Staphylococcus aureus make up a large proportion of human infections worldwide, causing various diseases that range from acute skin infections to life-threatening systemic toxic shock syndromes. P85α, the regulatory subunit of Class IA PI3K and necessary for PI(3,4,5)P3 production, remains associated with the phagosome membrane even when PI(3,4,5)P3 is no longer present [21] These observations led us to hypothesize that p85α differentially influences extracellular and intracellular NADPH oxidase activity and performs a function on the internalized, sealed phagosome independent of PI(3,4,5)P3 production. Our work provides a novel target in the regulation of enhancing neutrophil intracellular ROS, which has been shown to cooperate with anti-microbial agents to increase bacterial killing [22, 23] This is an improvement over indiscriminately increasing global ROS production, which could lead to inflammation-induced tissue injury. Using intracellular ROS to augment anti-microbial therapies may provide a novel strategy in the treatment of antibioticresistant pathogens
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