Distinct mechanisms of type 3 secretion system recognition control LTB4 synthesis in neutrophils and macrophages.

IF 5.5 1区 医学 Q1 MICROBIOLOGY
PLoS Pathogens Pub Date : 2024-10-18 eCollection Date: 2024-10-01 DOI:10.1371/journal.ppat.1012651
Amanda Brady, Leonardo C Mora Martinez, Benjamin Hammond, Kaitlyn M Whitefoot-Keliin, Bodduluri Haribabu, Silvia M Uriarte, Matthew B Lawrenz
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引用次数: 0

Abstract

Leukotriene B4 (LTB4) is an inflammatory lipid produced in response to pathogens that is critical for initiating the inflammatory cascade needed to control infection. However, during plague, Yersinia pestis inhibits the timely synthesis of LTB4 and subsequent inflammation. Using bacterial mutants, we previously determined that Y. pestis inhibits LTB4 synthesis via the action of the Yop effector proteins that are directly secreted into host cells through a type 3 secretion system (T3SS). Here, we show that the T3SS is the primary pathogen associated molecular pattern (PAMP) required for production of LTB4 in response to both Yersinia and Salmonella. However, we also unexpectantly discovered that T3SS-mediated LTB4 synthesis by neutrophils and macrophages require the activation of two distinctly different host signaling pathways. We identified that phagocytosis and the NLRP3/CASP1 inflammasome significantly impact LTB4 synthesis by macrophages but not neutrophils. Instead, the SKAP2/PLC signaling pathway is required for T3SS-mediated LTB4 production by neutrophils. Finally, while recognition of the T3SS is required for LTB4 production, we also discovered that a second unrelated PAMP-mediated signal activates the MAP kinase pathway needed for synthesis. Together, these data demonstrate significant differences in the host factors and signaling pathways required by macrophages and neutrophils to quickly produce LTB4 in response to bacteria. Moreover, while macrophages and neutrophils might rely on different signaling pathways for T3SS-dependent LTB4 synthesis, Y. pestis has evolved virulence mechanisms to counteract this response by either leukocyte to inhibit LTB4 synthesis and colonize the host.

3型分泌系统识别控制中性粒细胞和巨噬细胞中LTB4合成的不同机制
白三烯 B4(LTB4)是一种针对病原体产生的炎症脂质,对于启动控制感染所需的炎症级联反应至关重要。然而,在鼠疫期间,鼠疫耶尔森氏菌会抑制 LTB4 的及时合成和随后的炎症反应。利用细菌突变体,我们先前确定鼠疫耶尔森菌通过 Yop 效应蛋白的作用抑制 LTB4 的合成,Yop 效应蛋白通过 3 型分泌系统(T3SS)直接分泌到宿主细胞中。在这里,我们发现 T3SS 是针对耶尔森菌和沙门氏菌产生 LTB4 所需的主要病原体相关分子模式(PAMP)。然而,我们还意外地发现,由中性粒细胞和巨噬细胞介导的 T3SS LTB4 合成需要激活两种截然不同的宿主信号通路。我们发现,吞噬作用和 NLRP3/CASP1 炎性体对巨噬细胞的 LTB4 合成有显著影响,但对中性粒细胞没有影响。相反,T3SS 介导的中性粒细胞 LTB4 生成需要 SKAP2/PLC 信号通路。最后,虽然 T3SS 的识别是产生 LTB4 所必需的,但我们还发现第二个与之无关的 PAMP 介导的信号激活了合成所需的 MAP 激酶途径。这些数据共同表明,巨噬细胞和中性粒细胞在应对细菌时快速产生 LTB4 所需的宿主因子和信号通路存在显著差异。此外,虽然巨噬细胞和中性粒细胞可能依赖不同的信号通路来进行依赖 T3SS 的 LTB4 合成,但 Y. pestis 已进化出毒力机制来抵消任一白细胞的这种反应,从而抑制 LTB4 合成并在宿主体内定殖。
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来源期刊
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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