Molecular Prerequisites for Neutrophil Extracellular Trap Formation and Evasion Mechanisms of Staphylococcus aureus.

Maren Von Köckritz-Blickwede,Volker Winstel

doi:10.3389/fimmu.2022.836278

Abstract

NETosis is a multi-facetted cellular process that promotes the formation of neutrophil extracellular traps (NETs). NETs as web-like structures consist of DNA fibers armed with granular proteins, histones, and microbicidal peptides, thereby exhibiting pathogen-immobilizing and antimicrobial attributes that maximize innate immune defenses against invading microbes. However, clinically relevant pathogens often tolerate entrapment and even take advantage of the remnants of NETs to cause persistent infections in mammalian hosts. Here, we briefly summarize how Staphylococcus aureus, a high-priority pathogen and causative agent of fatal diseases in humans as well as animals, catalyzes and concurrently exploits NETs during pathogenesis and recurrent infections. Specifically, we focus on toxigenic and immunomodulatory effector molecules produced by staphylococci that prime NET formation, and further highlight the molecular and underlying principles of suicidal NETosis compared to vital NET-formation by viable neutrophils in response to these stimuli. We also discuss the inflammatory potential of NET-controlled microenvironments, as excessive expulsion of NETs from activated neutrophils provokes local tissue injury and may therefore amplify staphylococcal disease severity in hospitalized or chronically ill patients. Combined with an overview of adaptation and counteracting strategies evolved by S. aureus to impede NET-mediated killing, these insights may stimulate biomedical research activities to uncover novel aspects of NET biology at the host-microbe interface.

Highlights

Polymorphonuclear leukocytes (PMNs or neutrophils) are highly abundant immune cells found in human or animal blood [1]
As aberrant NETosis is linked to severe staphylococcal infections and the establishment of pulmonary infections in chronically ill patients [16, 114], it is further tempting to speculate that S. aureus may take advantage of the organ-damaging capacities of neutrophil extracellular DNA traps (NETs) or NET-associated components to traverse endothelial or epithelial barriers for subsequent penetration of deep tissues
Concurrent stimulation and exploitation of excessive NETosis may represent a refined immune-evasive maneuver evolved by S. aureus to create new proliferative niches in the mammalian host, a fact that may clarify why staphylococci excrete a plethora of NET-inducing effector molecules into the extracellular space

Summary

INTRODUCTION

Polymorphonuclear leukocytes (PMNs or neutrophils) are highly abundant immune cells found in human or animal blood [1]. Subsequent steps involve disruption of the nuclear cell envelope and electrostatic interaction of core-derived decondensed chromatin with cytosolic and granular proteins in the cytoplasm (Figure 1) [23] In this scenario, the human cathelicidin LL-37 and its mouse analogue mCRAMP (mouse cathelicidin related antimicrobial peptide) have been shown to contribute to the perforation of nuclear membranes in NETforming neutrophils [36]. NET formation can be induced via a secondary mechanism which retains PMN integrity and viability by an active release of DNA-containing vesicles (Figure 1) This process (i.e. vital NET formation; sometimes referred to as vesicular NETosis) is mainly NADPH oxidase-independent and rapidly occurs within less than hour upon stimulation [43, 44]. Agr is a quorum sensing system that consists of several structural components including AgrD, the precursor molecule of the autoinducing peptide AIP which facilitates staphylococcal communication and target gene regulation via activation of AgrC-AgrA two component system [65]

CONCLUDING REMARKS

Findings

ETHICS STATEMENT