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Toll 样受体 4 信号通路导致严重的真菌感染,与增强的促炎免疫和调节性 T 细胞扩增受损有关。

Toll-like receptor 4 signaling leads to severe fungal infection associated with enhanced proinflammatory immunity and impaired expansion of regulatory T cells.

机构信息

Departamento de Imunologia, Instituto de Ciências Biomédicas da Universidade de São Paulo, CEP 05508-900, São Paulo, SP, Brazil.

出版信息

Infect Immun. 2010 Mar;78(3):1078-88. doi: 10.1128/IAI.01198-09. Epub 2009 Dec 14.

Abstract

Toll-like receptors (TLRs) present in innate immune cells recognize pathogen molecular patterns and influence immunity to control the host-parasite interaction. The objective of this study was to characterize the involvement of TLR4 in the innate and adaptive immunity to Paracoccidioides brasiliensis, the most important primary fungal pathogen of Latin America. We compared the responses of C3H/HeJ mice, which are naturally defective in TLR4 signaling, with those of C3H/HePas mice, which express functional receptors, after in vitro and in vivo infection with P. brasiliensis. Unexpectedly, we verified that TLR4-defective macrophages infected in vitro with P. brasiliensis presented decreased fungal loads associated with impaired synthesis of nitric oxide, interleukin-12 (IL-12), and macrophage chemotactic protein 1 (MCP-1). After intratracheal infection with 1 million yeasts, TLR4-defective mice developed reduced fungal burdens and decreased levels of pulmonary nitric oxide, proinflammatory cytokines, and antibodies. TLR4-competent mice produced elevated levels of IL-12 and tumor necrosis factor alpha (TNF-alpha), besides cytokines of the Th17 pattern, indicating a proinflammatory role for TLR4 signaling. The more severe infection of TLR4-normal mice resulted in increased influx of activated macrophages and T cells to the lungs and progressive control of fungal burdens but impaired expansion of regulatory T cells (Treg cells). In contrast, TLR4-defective mice were not able to clear their diminished fungal burdens totally, a defect associated with deficient activation of T-cell immunity and enhanced development of Treg cells. These divergent patterns of immunity, however, resulted in equivalent mortality rates, indicating that control of elevated fungal growth mediated by vigorous inflammatory reactions is as deleterious to the hosts as low fungal loads inefficiently controlled by limited inflammatory reactions.

摘要

Toll 样受体(TLRs)存在于先天免疫细胞中,可识别病原体分子模式,并影响免疫反应以控制宿主-寄生虫相互作用。本研究的目的是研究 TLR4 在巴西副球孢子菌固有和适应性免疫中的作用,巴西副球孢子菌是拉丁美洲最重要的原发性真菌病原体。我们比较了 C3H/HeJ 小鼠(其 TLR4 信号传导天然缺陷)和 C3H/HePas 小鼠(表达功能性受体)在体外和体内感染巴西副球孢子菌后的反应。出乎意料的是,我们发现体外感染巴西副球孢子菌的 TLR4 缺陷型巨噬细胞的真菌负荷降低,与一氧化氮、白细胞介素-12(IL-12)和巨噬细胞趋化蛋白 1(MCP-1)的合成受损有关。经气管内感染 100 万个酵母后,TLR4 缺陷型小鼠的真菌负荷降低,肺一氧化氮、促炎细胞因子和抗体水平降低。TLR4 功能正常的小鼠产生更高水平的白细胞介素-12(IL-12)和肿瘤坏死因子-α(TNF-α),以及 Th17 模式的细胞因子,表明 TLR4 信号传导具有促炎作用。TLR4 正常小鼠更严重的感染导致激活的巨噬细胞和 T 细胞向肺部的流入增加,并逐渐控制真菌负荷,但调节性 T 细胞(Treg 细胞)的扩增受损。相比之下,TLR4 缺陷型小鼠不能完全清除其减少的真菌负荷,这种缺陷与 T 细胞免疫的激活不足以及 Treg 细胞的过度发育有关。然而,这些不同的免疫模式导致了相当的死亡率,这表明由强烈炎症反应介导的对真菌生长的控制对宿主同样有害,就像由有限炎症反应低效控制的低真菌负荷一样。

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