Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk.
Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk.
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DOI：
10.1038/nature13489
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发表时间：
2014-07-03
期刊：
影响因子：
64.8
通讯作者：
Sher A
中科院分区：
文献类型：
--
作者：
Mayer-Barber KD;Andrade BB;Oland SD;Amaral EP;Barber DL;Gonzales J;Derrick SC;Shi R;Kumar NP;Wei W;Yuan X;Zhang G;Cai Y;Babu S;Catalfamo M;Salazar AM;Via LE;Barry CE 3rd;Sher A
结核病仍然是仅次于艾滋病毒/艾滋病的世界范围内因单一感染源而导致死亡的主要原因。尽管进行了化疗，但由于艾滋病毒合并感染、缺乏有效疫苗以及出现多药耐药细菌，全球结核病疫情加剧。可以利用替代的宿主导向策略来提高治疗效果和结果，遏制耐药菌株，降低疾病严重程度和死亡率。结核分枝杆菌(Mtb)引起的先天炎症反应是一种合乎逻辑的宿主靶点。在这里，我们证明了白介素1(IL-1)通过诱导二十烷基类化合物来诱导宿主抵抗，从而限制过量的I型干扰素(干扰素)的产生并促进细菌的遏制。我们进一步证明，在感染的小鼠和患者中，IL-1反应减少和/或过量的I型干扰素诱导与疾病恶化相关的二十烷类激素失衡有关。在这些环境中，用临床批准的药物提高前列腺素E2水平的宿主定向免疫疗法防止了结核分枝杆菌感染小鼠的急性死亡。因此，IL-1和I型IFN代表了两类主要的反调节炎性细胞因子，它们控制着结核分枝杆菌感染的结果，并通过二十烷类化合物在功能上联系在一起。我们的发现为宿主导向治疗策略建立了概念证据，这种策略操纵宿主二十烷酸网络，并代表了常规化疗的可行替代方案。
Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent. Despite chemotherapy, the global tuberculosis epidemic has intensified because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target. Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy.