Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins

Zhou, Quan; Chi, Xun; Lee, Min Sub; Hsieh, Wei Yuan; Mkrtchyan, Jonathan J.; Feng, An‐Chieh; He, Cuiwen; York, Autumn G.; Bui, Viet L.; Kronenberger, Eliza B.; Ferrari, Alessandra; Xu, Xiao; Daly, Allison E.; Tarling, Elizabeth J.; Damoiseaux, Robert; Scumpia, Philip O.; Smale, Stephen T.; Williams, Kevin J.; Tontonoz, Peter; Bensinger, Steven J.

doi:10.1038/s41590-020-0695-4

Cited by 68 publications

(129 citation statements)

References 56 publications

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“…Both innate cellular defenses and therapeutic remedies exploit this sterol dependence to combat such infections 63 . It was shown recently that cells reduce their susceptibility to certain bacteria and toxins by downregulating active plasma membrane cholesterol 64,65 …”

Section: Active Cholesterolmentioning

confidence: 99%

Active cholesterol 20 years on

Lange

Steck

2020

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This review considers the following hypotheses, some well‐supported and some speculative. Almost all of the sterol molecules in plasma membranes are associated with bilayer phospholipids in complexes of varied strength and stoichiometry. These complexes underlie many of the material properties of the bilayer. The small fraction of cholesterol molecules exceeding the binding capacity of the phospholipids is thermodynamically active and serves diverse functions. It circulates briskly among the cell membranes, particularly through contact sites linking the organelles. Active cholesterol provides the upstream feedback signal to multiple mechanisms governing plasma membrane homeostasis, pegging the sterol level to a threshold set by its phospholipids. Active cholesterol could also be the cargo for various inter‐organelle transporters and the form excreted from cells by reverse transport. Furthermore, it is integral to the function of caveolae; a mediator of Hedgehog regulation; and a ligand for the binding of cytolytic toxins to membranes. Active cholesterol modulates a variety of plasma membrane proteins—receptors, channels and transporters—at least in vitro.

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Section: Active Cholesterolmentioning

confidence: 99%

Active cholesterol 20 years on

Lange

Steck

2020

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“…This reduction in accessible cholesterol prevents the intercellular spread of L. monocytogenes [159], presumably due to reduced ability of LLO to damage the plasma membrane. Indeed, PFO, ALO, and SLO all show reduced binding and membrane damage in IFN-stimulated macrophages, which is due to 25-hydroxy-cholesterol reducing the fraction of CDC-accessible cholesterol [160]. In a skin model, 25-hydroxy-cholesterol reduced the extent of damage from CDCs [160].…”

Section: Cdcs Activate the Inflammasomementioning

confidence: 98%

“…Indeed, PFO, ALO, and SLO all show reduced binding and membrane damage in IFN-stimulated macrophages, which is due to 25-hydroxy-cholesterol reducing the fraction of CDC-accessible cholesterol [160]. In a skin model, 25-hydroxy-cholesterol reduced the extent of damage from CDCs [160]. Thus, immune cells use oxysterols to modify their plasma membrane cholesterol to protect their plasma membrane and the plasma membrane and the barrier function of non-immune cells as well as to limit inflammasome activation.…”

Section: Cdcs Activate the Inflammasomementioning

confidence: 99%

“…ALO may promote gut epithelial disruption, much like PFO [101]. As with PFO, the domain 4 of ALO has been used to detect cholesterol on the plasma membrane of cells, including macrophages [160,273,274] However, the domain 4 of ALO may be more stable and better tolerate maleimide-based fluorophore addition than the PFO domain 4 [94,160,273], so it is emerging as the preferred CDC-derived cholesterol sensor over PFO. TLO, produced by Clostridium tetani, is presumed to contribute to C. tetani pathogenesis by destroying host cells.…”

Section: Anthrolysin O (Alo) Tetanolysin O (Tlo) and Suilysin (Sly)mentioning

confidence: 99%

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Interaction of Macrophages and Cholesterol-Dependent Cytolysins: The Impact on Immune Response and Cellular Survival

Thapa

Ray

Keyel

2020

Toxins

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Cholesterol-dependent cytolysins (CDCs) are key virulence factors involved in many lethal bacterial infections, including pneumonia, necrotizing soft tissue infections, bacterial meningitis, and miscarriage. Host responses to these diseases involve myeloid cells, especially macrophages. Macrophages use several systems to detect and respond to cholesterol-dependent cytolysins, including membrane repair, mitogen-activated protein (MAP) kinase signaling, phagocytosis, cytokine production, and activation of the adaptive immune system. However, CDCs also promote immune evasion by silencing and/or destroying myeloid cells. While there are many common themes between the various CDCs, each CDC also possesses specific features to optimally benefit the pathogen producing it. This review highlights host responses to CDC pathogenesis with a focus on macrophages. Due to their robust plasticity, macrophages play key roles in the outcome of bacterial infections. Understanding the unique features and differences within the common theme of CDCs bolsters new tools for research and therapy.

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“…Overall, membrane-targeting immune evasion strategies are important drivers of septic courses. Of note, neutrophils can become resistant against some cytolysins by reprogramming the membrane cholesterol composition [121]. Important representatives for DAMPs are histones and extracellular ATP.…”

Section: Alteration Of the Membrane Integrity By Mamps And Dampsmentioning

confidence: 99%

Ion and Water Transport in Neutrophil Granulocytes and Its Impairment during Sepsis

Messerer

Schmidt

Frick

et al. 2021

IJMS

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Neutrophil granulocytes are the vanguard of innate immunity in response to numerous pathogens. Their activity drives the clearance of microbe- and damage-associated molecular patterns, thereby contributing substantially to the resolution of inflammation. However, excessive stimulation during sepsis leads to cellular unresponsiveness, immunological dysfunction, bacterial expansion, and subsequent multiple organ dysfunction. During the short lifespan of neutrophils, they can become significantly activated by complement factors, cytokines, and other inflammatory mediators. Following stimulation, the cells respond with a defined (electro-)physiological pattern, including depolarization, calcium influx, and alkalization as well as with increased metabolic activity and polarization of the actin cytoskeleton. Activity of ion transport proteins and aquaporins is critical for multiple cellular functions of innate immune cells, including chemotaxis, generation of reactive oxygen species, and phagocytosis of both pathogens and tissue debris. In this review, we first describe the ion transport proteins and aquaporins involved in the neutrophil ion–water fluxes in response to chemoattractants. We then relate ion and water flux to cellular functions with a focus on danger sensing, chemotaxis, phagocytosis, and oxidative burst and approach the role of altered ion transport protein expression and activity in impaired cellular functions and cell death during systemic inflammation as in sepsis.

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Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins

Cited by 68 publications

References 56 publications

Active cholesterol 20 years on

Active cholesterol 20 years on

Interaction of Macrophages and Cholesterol-Dependent Cytolysins: The Impact on Immune Response and Cellular Survival

Ion and Water Transport in Neutrophil Granulocytes and Its Impairment during Sepsis

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