Abstract
Regulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage. Pseudomonas aeruginosa expresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial elimination in vitro and in vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogen Burkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology.
Highlights
Regulated cell necrosis (RCNs) drives physiological and immune processes, yet dysregulation of this process promotes pathological responses such as organ-failure and sepsis [1,2,3,4]
A proper activation of various regulated cell necrosis confer a significant advantage against various infectious agents, their dysregulation drives host tissue damages that can end up with fatal sepsis
30% of the bacterial strains of Pseudomonas aeruginosa (P. aeruginosa) express the phospholipase A2-like toxin ExoU that is injected into host target cells through the Type-3 Secretion System
Summary
Regulated cell necrosis (RCNs) drives physiological and immune processes, yet dysregulation of this process promotes pathological responses such as organ-failure and sepsis [1,2,3,4]. The dysregulation of lipid peroxidation processes is associated with various human pathologies such as cancer chemoresistance, brain and ischemia injuries, neurological alterations, metabolic diseases as well as tuberculosis susceptibility [18,19,20,21,22,23]. In this context, the enzymes glutathione peroxidase 4 (GPX4) and ferroptosis-suppressor protein-1 (FSP1) that belongs to the CoQ antioxidant system, detoxify phospholipid hydroperoxide accumulation, allowing lipid peroxide amounts to be balanced in cells [5,11,12,14,24]. Iron excess, lipoxygenase activity or cytochrome P450 oxidoreductase (CYPOR) all promote phospholipid peroxidation, which can end with ferroptosis induction in the absence of proper regulation [5,14,15,16,25,26]
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