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Cholesterol-dependent cytolysins impair pro-inflammatory macrophage responses.

ABSTRACT: Necrotizing soft tissue infections are lethal polymicrobial infections. Two key microbes that cause necrotizing soft tissue infections are Streptococcus pyogenes and Clostridium perfringens. These pathogens evade innate immunity using multiple virulence factors, including cholesterol-dependent cytolysins (CDCs). CDCs are resisted by mammalian cells through the sequestration and shedding of pores during intrinsic membrane repair. One hypothesis is that vesicle shedding promotes immune evasion by concomitantly eliminating key signaling proteins present in cholesterol-rich microdomains. To test this hypothesis, murine macrophages were challenged with sublytic CDC doses. CDCs suppressed LPS or IFN?-stimulated TNF? production and CD69 and CD86 surface expression. This suppression was cell intrinsic. Two membrane repair pathways, patch repair and intrinsic repair, might mediate TNF? suppression. However, patch repair did not correlate with TNF? suppression. Intrinsic repair partially contributed to macrophage dysfunction because TLR4 and the IFN?R were partially shed following CDC challenge. Intrinsic repair was not sufficient for suppression, because pore formation was also required. These findings suggest that even when CDCs fail to kill cells, they may impair innate immune signaling responses dependent on cholesterol-rich microdomains. This is one potential mechanism to explain the lethality of S. pyogenes and C. perfringens during necrotizing soft tissue infections.

SUBMITTER: Bhattacharjee P

PROVIDER: S-EPMC5915385 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Cholesterol-dependent cytolysins impair pro-inflammatory macrophage responses.

Bhattacharjee Pushpak P Keyel Peter A PA

Scientific reports 20180424 1

Necrotizing soft tissue infections are lethal polymicrobial infections. Two key microbes that cause necrotizing soft tissue infections are Streptococcus pyogenes and Clostridium perfringens. These pathogens evade innate immunity using multiple virulence factors, including cholesterol-dependent cytolysins (CDCs). CDCs are resisted by mammalian cells through the sequestration and shedding of pores during intrinsic membrane repair. One hypothesis is that vesicle shedding promotes immune evasion by ...[more]

PMID: 29691463

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Project description:Bacterial vaginosis (BV) is a vaginal anaerobic dysbiosis that affects women of reproductive age worldwide. BV is microbiologically characterized by the depletion of vaginal lactobacilli and the overgrowth of anaerobic bacterial species. Accumulated evidence suggests that Gardnerella spp. have a pivotal role among BV-associated bacteria in the initiation and development of BV. However, Gardnerella spp. often colonize healthy women. Lactobacillus iners is considered as a prevalent constituent of healthy vaginal microbiota, and is abundant in BV. Gardnerella spp. and L. iners secrete the toxins vaginolysin (VLY) and inerolysin (INY), which have structural and activity features attributed to cholesterol-dependent cytolysins (CDCs). CDCs are produced by many pathogenic bacteria as virulence factors that participate in various stages of disease progression by forming lytic and non-lytic pores in cell membranes or via pore-independent pathways. VLY is expressed in the majority of Gardnerella spp. isolates; less is known about the prevalence of the gene that encodes INY. INY is a classical CDC; membrane cholesterol acts a receptor for INY. VLY uses human CD59 as its receptor, although cholesterol remains indispensable for VLY pore-forming activity. INY-induced damage of artificial membranes is directly dependent on cholesterol concentration in the bilayer, whereas VLY-induced damage occurs with high levels of membrane cholesterol (>40 mol%). VLY primarily forms membrane-embedded complete rings in the synthetic bilayer, whereas INY forms arciform structures with smaller pore sizes. VLY activity is high at elevated pH, which is characteristic of BV, whereas INY activity is high at more acidic pH, which is specific for a healthy vagina. Increased VLY levels in vaginal mucosa in vivo were associated with clinical indicators of BV. However, experimental evidence is lacking for the specific roles of VLY and INY in BV. The interplay between vaginal bacterial species affects the expression of the gene encoding VLY, thereby modulating the virulence of Gardnerella spp. This review discusses the current evidence for VLY and INY cytolysins, including their structures and activities, factors affecting their expression, and their potential impacts on the progression of anaerobic dysbiosis.

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Cholesterol-dependent cytolysins impair pro-inflammatory macrophage responses.

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Cholesterol-dependent cytolysins impair pro-inflammatory macrophage responses.

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