TLR-Dependent Control of Francisella tularensis Infection and Host Inflammatory Responses
TLR-Dependent Control of Francisella tularensis Infection and Host Inflammatory Responses
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DOI：
10.1371/journal.pone.0007920
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发表时间：
2009-11-20
期刊：
影响因子：
3.7
通讯作者：
Berton, Michael T.
中科院分区：
文献类型：
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作者：
Abplanalp, Allison L.;Morris, Ian R.;Berton, Michael T.
背景：土拉弗朗西斯菌是兔热病的病原体，被列为 A 类选择病原体。最近的研究表明，TLR2 是宿主对土拉弗朗西斯菌感染的保护性反应中的关键因素，但仍存在疑问：TLR2 信号传导是否在所有情况下和所有弗朗西斯菌物种中主导反应，以及土拉弗朗西斯菌 PAMP 是否主要被 TLR2/TLR1 或 TLR2/TLR6 识别。为了解决这些问题，我们探索了 Toll 样受体 (TLR) 在宿主对土拉弗朗西斯活疫苗株 (LVS) 和土拉弗朗西斯亚种 (subsp.) 新杀者感染的宿主反应中的作用。方法学/主要发现：C57BL/6 (B6) 对照小鼠和 TLR 或 MyD88 缺陷小鼠通过鼻内 (i.n.) 或皮内 (i.d.) 使用 F. tularensis LVS 或 F. tularensis subsp.新手。 B6 小鼠通过两种途径感染 LVS 后存活 >21 天，而 TLR1(-/-)、TLR4(-/-) 和 TLR6(-/-) 小鼠体内感染的存活率也相同。使用 LVS 相当于对照。然而，与 B6 小鼠相比，TLR2(-/-) 和 MyD88(-/-) 小鼠的存活率显着降低，无论感染途径或土拉弗拉菌亚种如何。与对照组相比，TLR2(-/-) 和 MyD88(-/-) 小鼠的肺、肝和脾脏中的细菌负荷也有所增加。感染。在体外感染 LVS 后，MyD88(-/-) 和 TLR2(-/-) 小鼠的原代巨噬细胞分泌 TNF 和其他促炎细胞因子的能力显着受损。通过支气管肺泡灌洗液分析和原位免疫荧光染色证明，TNF 表达在体内也受到损害。结论/意义：我们从这些研究中得出结论，TLR2 和 MyD88，而不是 TLR4，在土拉弗朗西斯感染的先天免疫反应中发挥关键作用，无论感染途径或亚种如何。此外，在土拉弗朗西斯 LVS 感染期间，通过 TLR2 的信号传导并不完全依赖于 TLR1 或 TLR6。
Background: Francisella tularensis is the causative agent of tularemia and is classified as a Category A select agent. Recent studies have implicated TLR2 as a critical element in the host protective response to F. tularensis infection, but questions remain about whether TLR2 signaling dominates the response in all circumstances and with all species of Francisella and whether F. tularensis PAMPs are predominantly recognized by TLR2/TLR1 or TLR2/TLR6. To address these questions, we have explored the role of Toll-like receptors (TLRs) in the host response to infections with F. tularensis Live Vaccine Strain (LVS) and F. tularensis subspecies (subsp.) novicida in vivo.Methodology/Principal Findings: C57BL/6 (B6) control mice and TLR-or MyD88-deficient mice were infected intranasally (i.n.) or intradermally (i.d.) with F. tularensis LVS or with F. tularensis subsp. novicida. B6 mice survived >21 days following infection with LVS by both routes and survival of TLR1(-/-), TLR4(-/-), and TLR6(-/-) mice infected i.n. with LVS was equivalent to controls. Survival of TLR2(-/-) and MyD88(-/-) mice, however, was significantly reduced compared to B6 mice, regardless of the route of infection or the subspecies of F. tularensis. TLR2(-/-) and MyD88(-/-) mice also showed increased bacterial burdens in lungs, liver, and spleen compared to controls following i.n. infection. Primary macrophages from MyD88(-/-) and TLR2(-/-) mice were significantly impaired in the ability to secrete TNF and other pro-inflammatory cytokines upon ex vivo infection with LVS. TNF expression was also impaired in vivo as demonstrated by analysis of bronchoalveolar lavage fluid and by in situ immunofluorescent staining.Conclusions/Significance: We conclude from these studies that TLR2 and MyD88, but not TLR4, play critical roles in the innate immune response to F. tularensis infection regardless of the route of infection or the subspecies. Moreover, signaling through TLR2 does not depend exclusively on TLR1 or TLR6 during F. tularensis LVS infection.