Heat-Labile Enterotoxin Decreases Macrophage Phagocytosis of Enterotoxigenic Escherichia coli.
Heat-Labile Enterotoxin Decreases Macrophage Phagocytosis of Enterotoxigenic Escherichia coli.
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DOI：
10.3390/microorganisms11082121
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发表时间：
2023-08-21
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
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产肠毒素大肠大肠杆菌（ETEC）是低资源环境中的地方病，并在5岁以下的儿童中引起严重的分泌性腹泻病。ETEC通过产生热稳定（ST）和/或热不稳定（LT）肠毒素引起分泌性腹泻。最近的研究表明，ETEC可以在儿童和成人中无症状地携带，但ETEC如何破坏粘膜免疫以建立肠道驻留仍不清楚。巨噬细胞是先天性免疫细胞，可以被肠道病原体利用来逃避粘膜免疫，因此我们研究了ETEC和其他E。大肠杆菌致病变种在巨噬细胞内存活。使用庆大霉素保护试验，我们表明ETEC H10407比其他ETEC和非ETEC分离株更容易被吞噬。此外，我们证明了ETEC H10407在高细菌负荷下会导致巨噬细胞中的亚硝酸盐积累，这表明巨噬细胞的促炎性一氧化氮杀伤反应。然而，在低细菌负荷下，ETEC H10407在巨噬细胞内可长时间保持活力，而无亚硝酸盐蓄积。我们证明LT而不是ST中毒减少了巨噬细胞吞噬的ETEC数量。此外，我们现在表明，巨噬细胞同时暴露于LPS和LT产生IL-33，这是一种细胞因子，涉及促进巨噬细胞替代激活，铁循环和肠道修复。最后，使用去铁胺的铁限制诱导IL-33受体（IL-33 R）表达，并允许ETEC逃离巨噬细胞。总之，这些数据表明LT为ETEC提供了降低感知ETEC负荷并抑制炎症发生的能力。此外，这些数据表明，宿主IL-33/IL-33 R信号传导可能增强促进铁限制的途径，以促进ETEC从巨噬细胞逃逸。这些数据有助于解释可能导致无症状ETEC携带的免疫破坏的新机制。
Enterotoxigenic E. coli (ETEC) are endemic in low-resource settings and cause robust secretory diarrheal disease in children less than five years of age. ETEC cause secretory diarrhea by producing the heat-stable (ST) and/or heat-labile (LT) enterotoxins. Recent studies have shown that ETEC can be carried asymptomatically in children and adults, but how ETEC subvert mucosal immunity to establish intestinal residency remains unclear. Macrophages are innate immune cells that can be exploited by enteric pathogens to evade mucosal immunity, so we interrogated the ability of ETEC and other E. coli pathovars to survive within macrophages. Using gentamicin protection assays, we show that ETEC H10407 is phagocytosed more readily than other ETEC and non-ETEC isolates. Furthermore, we demonstrate that ETEC H10407, at high bacterial burdens, causes nitrite accumulation in macrophages, which is indicative of a proinflammatory macrophage nitric oxide killing response. However, at low bacterial burdens, ETEC H10407 remains viable within macrophages for an extended period without nitrite accumulation. We demonstrate that LT, but not ST, intoxication decreases the number of ETEC phagocytosed by macrophages. Furthermore, we now show that macrophages exposed simultaneously to LPS and LT produce IL-33, which is a cytokine implicated in promoting macrophage alternative activation, iron recycling, and intestinal repair. Lastly, iron restriction using deferoxamine induces IL-33 receptor (IL-33R) expression and allows ETEC to escape macrophages. Altogether, these data demonstrate that LT provides ETEC with the ability to decrease the perceived ETEC burden and suppresses the initiation of inflammation. Furthermore, these data suggest that host IL-33/IL-33R signaling may augment pathways that promote iron restriction to facilitate ETEC escape from macrophages. These data could help explain novel mechanisms of immune subversion that may contribute to asymptomatic ETEC carriage.
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