Nonpathogenic SIV and Pathogenic HIV Infections Associate with Disparate Innate Cytokine Signatures in Response to Mycobacterium bovis BCG.
Nonpathogenic SIV and Pathogenic HIV Infections Associate with Disparate Innate Cytokine Signatures in Response to Mycobacterium bovis BCG.
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DOI：
10.1371/journal.pone.0158149
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Sodora DL
中科院分区：
文献类型：
--
作者：
Gasper MA;Biswas SP;Fisher BS;Ehnert SC;Sherman DR;Sodora DL
分枝杆菌感染，包括结核分枝杆菌 (Mtb) 和牛分枝杆菌 (M. bovis) BCG，是 HIV 感染者发病和死亡的主要原因。与 HIV 相比，乌白眉猴的非致病性 SIV 感染的特点是不存在临床疾病，包括不存在机会性感染。本研究的目的是通过比较致病性 HIV 或非致病性 SIV 感染期间的功能反应，确定非致病性慢病毒感染期间对牛支原体 BCG 维持的先天免疫反应。在离体 BCG 暴露 6 小时后，评估单核细胞表达关键抗分枝杆菌细胞因子 TNF-α 和 IL-12 的能力。 HIV 感染与产生 IL-12 的单核细胞百分比下降相关，而非致病性 SIV 感染则与产生两种细胞因子的单核细胞百分比增加相关。体外 BCG 暴露后的 PBMC 基因表达分析发现，HIV 感染者和对照受试者之间 NK 细胞相关基因和多种细胞因子（包括 IFN-γ 和 IL-23）的差异表达。相比之下，SIV 感染和未感染的对照白眉猴在接触 BCG 后基因表达没有显着差异。最后，确定了物种之间的差异基因表达模式，与人类相比，白眉猴对卡介苗的反应表现出较低的 IL-6 和较高的 IL-17。总体而言，对牛支原体 BCG 免疫反应的比较发现了独特的免疫特征（涉及细胞因子 IL-12、TNF-α、IL-23、IL-17 和 IL-6），这些特征在 HIV 期间发生改变，但在非致病性 SIV 感染期间保持或增加。这些独特的细胞因子和转录组特征提供了对致病性 HIV 感染期间对分枝杆菌的差异免疫反应的深入了解，这可能与分枝杆菌合并感染发生率的增加有关。
Infections with mycobacteria, including Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis (M. bovis) BCG, are a leading cause of morbidity and mortality for HIV-infected persons. In contrast to HIV, nonpathogenic SIV infections of sooty mangabeys are characterized by a lack of clinical disease including an absence of opportunistic infections. The goal of this study was to identify innate immune responses to M. bovis BCG maintained during nonpathogenic lentiviral infections through a comparison of functional responses during pathogenic HIV or nonpathogenic SIV infections. Monocytes were evaluated for their ability to express key anti-mycobacterial cytokines TNF-α and IL-12 following a six-hour ex vivo BCG exposure. While HIV-infection was associated with a decreased percentage of IL-12-producing monocytes, nonpathogenic SIV-infection was associated with an increased percentage of monocytes producing both cytokines. Gene expression analysis of PBMC following ex vivo BCG exposure identified differential expression of NK cell-related genes and several cytokines, including IFN-γ and IL-23, between HIV-infected and control subjects. In contrast, SIV-infected and uninfected-control mangabeys exhibited no significant differences in gene expression after BCG exposure. Finally, differential gene expression patterns were identified between species, with mangabeys exhibiting lower IL-6 and higher IL-17 in response to BCG when compared to humans. Overall, this comparison of immune responses to M. bovis BCG identified unique immune signatures (involving cytokines IL-12, TNF-α, IL-23, IL-17, and IL-6) that are altered during HIV, but maintained or increased during nonpathogenic SIV infections. These unique cytokine and transcriptome signatures provide insight into the differential immune responses to Mycobacteria during pathogenic HIV-infection that may be associated with an increased incidence of mycobacterial co-infections.