Mechanisms regulating Staphylococcus aureus strain-specific NADPH oxidase-dependent and -independent NETosis

Abstract

Neutrophil extracellular trap (NET) formation (NETosis) is the newest effector function ascribed to neutrophils, during the last decade. Neutrophils generate NETs with their own DNA fibers that are coated with intracellular cytotoxic compounds. NETs have the capacity to trap and kill pathogens, extracellularly. NETosis is a programmed cell death that is different from apoptosis and necrosis. However, during "early or vital NETosis", neutrophils survive after generating NETs. This type of NETosis is different from "classical NETosis", in which neutrophils die upon releasing NETs. Two major types of classical NETosis have been described to date: NADPH oxidase (Nox)-dependent and Nox-independent NETosis. Neutrophils generate NETs via Nox-dependent NETosis in response to many bacteria. This pathway depends on Nox generating large amounts of reactive oxygen species (ROS), and subsequent activation of specific sets of kinases. The second type of NETosis is Nox-independent NETosis. This type of NETosis primarily requires the increase in intracellular calcium, and citrullination of histones. Dr. Palaniyar's laboratory recently described that calcium-dependent potassium channel SK3, activation of Akt and mitochondrial ROS production are essential for Nox-independent NETosis. His lab also showed that inhibition of Akt during NETosis re-directs the cell death to apoptosis. Dr. Palaniyar's group also showed that Staphylococcus aureus strain RN4220 induces Nox-dependent NETosis, whereas others showed that S. aureus ATCC 25923 that produces penton valentine toxin [8] induces "early NETosis". However, how different stains of S. aureus induce different types of NETosis is not clearly established. Dr. Palaniyar's team is investigating the molecular mechanisms regulating different types of NETosis. The aim of our project is to investigate the molecular mechanisms of neutrophil activation in vital and classical NETosis using different strains of S. aureus. These studies will help us better understand distinct mechanisms of NETsosis, and could help to correctly treat infections caused by different strains of S. aureus. (AU)