Neisseria gonorrhoeae effectively blocks HIV-1 replication by eliciting a potent TLR9-dependent interferon-α response from plasmacytoid dendritic cells
Neisseria gonorrhoeae effectively blocks HIV-1 replication by eliciting a potent TLR9-dependent interferon-α response from plasmacytoid dendritic cells
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DOI：
10.1111/j.1462-5822.2010.01502.x
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发表时间：
2010-12-01
影响因子：
3.4
通讯作者：
Gray-Owen, Scott D.
中科院分区：
文献类型：
--
作者：
Dobson-Belaire, Wendy N.;Rebbapragada, Anuradha;Gray-Owen, Scott D.
P>临床和流行病学研究提供了淋病奈瑟菌感染与HIV传播之间正相关的证据；然而，检验这种关系的机制研究却得出了相互矛盾的结果。为了探索这种相互作用，我们将急性 HIV+ 个体的离体培养外周血细胞暴露于淋病奈瑟菌。出乎意料的是，我们在离体培养物中观察到 HIV-1 复制受到严重抑制，并且当来自健康捐献者的外周血单核细胞 (PBMC) 与 HIV-1 和淋病奈瑟菌共同感染时，这一情况得到了重现。接下来，我们确定淋球菌感染的 PBMC 释放出一种可有效阻止 HIV-1 复制的可溶性因子。细胞因子分析和抗体阻断实验表明，I 型干扰素、干扰素-α (IFN α) 在接触淋病奈瑟菌后表达，并负责抑制 HIV-1。细胞内染色、TLR9 阻断和基于细胞耗竭的研究表明，浆细胞样树突状细胞 (pDC) 以 TLR9 依赖性方式诱导 IFN α。鉴于 pDC 在针对细胞内病原体的先天防御中发挥了更重要的作用，pDC 对淋病奈瑟菌的反应是出乎意料的，这表明这可能是一种细菌免疫逃避策略。在艾滋病毒的背景下，这克服了病毒对干扰素反应的有效避免，并代表了这两种性传播病原体之间以前未被认识到的交叉点。
P>Clinical and epidemiological research provides evidence for a positive correlation between Neisseria gonorrhoeae infection and HIV transmission; however, mechanistic studies examining this relationship have yielded conflicting results. To explore this interaction, we exposed ex vivo cultured peripheral blood cells from acute HIV+ individuals to N. gonorrhoeae. Unexpectedly, we observed a profound inhibition in HIV-1 replication in the ex vivo cultures, and this was recapitulated when peripheral blood mononuclear cells (PBMCs) from healthy donors were co-infected with HIV-1 and N. gonorrhoeae. Next, we established that gonococcal-infected PBMCs liberated a soluble factor that effectively blocked HIV-1 replication. Cytokine analyses and antibody blocking experiments revealed that the type I interferon, interferon-alpha (IFN alpha), was expressed upon exposure to N. gonorrhoeae and was responsible for the inhibition of HIV-1. Intracellular staining, TLR9-blocking and cell depletion-based studies demonstrated that the IFN alpha was elicited by plasmacytoid dendritic cells (pDCs) in a TLR9-dependent manner. The pDC response to N. gonorrhoeae was unexpected given pDCs more established role in innate defence against intracellular pathogens, suggesting this may be a bacterial immune evasion strategy. In the context of HIV, this overcomes the virus's otherwise effective avoidance of the interferon response and represents a previously unrecognized intersection between these two sexually transmitted pathogens.