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Cholesterol-dependent cytolysins impair pro-inflammatory macrophage responses
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Journal Article
Cholesterol-dependent cytolysins impair pro-inflammatory macrophage responses
2018
Overview
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 IFNγ-stimulated TNFα production and CD69 and CD86 surface expression. This suppression was cell intrinsic. Two membrane repair pathways, patch repair and intrinsic repair, might mediate TNFα suppression. However, patch repair did not correlate with TNFα suppression. Intrinsic repair partially contributed to macrophage dysfunction because TLR4 and the IFNγR 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/21
/ 13/31
/ 96/34
/ Animals
/ Antigens, Differentiation, T-Lymphocyte - metabolism
/ Bacterial Proteins - metabolism
/ Bacterial Toxins - metabolism
/ Clostridium perfringens - metabolism
/ Clostridium perfringens - pathogenicity
/ Female
/ Hemolysin Proteins - metabolism
/ Humanities and Social Sciences
/ Immunity, Innate - immunology
/ Immunity, Innate - physiology
/ Lectins, C-Type - metabolism
/ Male
/ Mice
/ Science
/ Signal Transduction - drug effects
/ Streptococcus pyogenes - metabolism
/ Streptococcus pyogenes - pathogenicity
