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Abstract：
BACKGROUND: Helminth infections are widespread in tuberculosis-endemic areas and are associated with an increased risk of active tuberculosis. In contrast to the pro-inflammatory Th1 responses elicited by Mycobacterium tuberculosis (Mtb) infection, helminth infections induce anti-inflammatory Th2/Treg responses. A robust Th2 response has been linked to reduced tuberculosis protection. Several studies show the effect of helminth infection on BCG vaccination and TB, but the mechanisms remain unclear.
OBJECTIVE: To determine the cytokine response profiles during tuberculosis and intestinal helminth coinfection.
METHODS: For the in vitro study, lymphocytic Jurkat and monocytic THP-1 cell lines were stimulated with Mtb H37Rv and Ascaris lumbricoides (A. lumbricoides) excretory-secretory protein extracts for 24 and 48 h. The pilot human ex vivo study consisted of participants infected with Mtb, helminths, or coinfected with both Mtb and helminths. Thereafter, the gene transcription levels of IFN-γ, TNF-α, granzyme B, perforin, IL-2, IL-17, NFATC2, Eomesodermin, IL-4, IL-5, IL-10, TGF-β and FoxP3 in the unstimulated/uninfected controls, singly stimulated/infected and costimulated/coinfected groups were determined using RT-qPCR.
RESULTS: TB-stimulated Jurkat cells had significantly higher levels of IFN-γ, TNF-α, granzyme B, and perforin compared to unstimulated controls, LPS- and A. lumbricoides-stimulated cells, and A. lumbricoides plus TB-costimulated cells (p < 0.0001). IL-2, IL-17, Eomes, and NFATC2 levels were also higher in TB-stimulated Jurkat cells (p < 0.0001). Jurkat and THP-1 cells singly stimulated with TB had lower IL-5 and IL-4 levels compared to those singly stimulated with A. lumbricoides and those costimulated with TB plus A. lumbricoides (p < 0.0001). A. lumbricoides-singly stimulated cells had higher IL-4 levels compared to TB plus A. lumbricoides-costimulated Jurkat and THP-1 cells (p < 0.0001). TGF-β levels were also lower in TB-singly stimulated cells compared to TB plus A. lumbricoides-costimulated cells (p < 0.0001). IL-10 levels were lower in TB-stimulated Jurkat and THP-1 cells compared to TB plus A. lumbricoides-costimulated cells (p < 0.0001). Similar results were noted for the human ex vivo study, albeit with a smaller sample size.
CONCLUSIONS: Data suggest that helminths induce a predominant Th2/Treg response which may downregulate critical Th1 responses that are crucial for tuberculosis protection.
OBJECTIVE: To determine the cytokine response profiles during tuberculosis and intestinal helminth coinfection.
METHODS: For the in vitro study, lymphocytic Jurkat and monocytic THP-1 cell lines were stimulated with Mtb H37Rv and Ascaris lumbricoides (A. lumbricoides) excretory-secretory protein extracts for 24 and 48 h. The pilot human ex vivo study consisted of participants infected with Mtb, helminths, or coinfected with both Mtb and helminths. Thereafter, the gene transcription levels of IFN-γ, TNF-α, granzyme B, perforin, IL-2, IL-17, NFATC2, Eomesodermin, IL-4, IL-5, IL-10, TGF-β and FoxP3 in the unstimulated/uninfected controls, singly stimulated/infected and costimulated/coinfected groups were determined using RT-qPCR.
RESULTS: TB-stimulated Jurkat cells had significantly higher levels of IFN-γ, TNF-α, granzyme B, and perforin compared to unstimulated controls, LPS- and A. lumbricoides-stimulated cells, and A. lumbricoides plus TB-costimulated cells (p < 0.0001). IL-2, IL-17, Eomes, and NFATC2 levels were also higher in TB-stimulated Jurkat cells (p < 0.0001). Jurkat and THP-1 cells singly stimulated with TB had lower IL-5 and IL-4 levels compared to those singly stimulated with A. lumbricoides and those costimulated with TB plus A. lumbricoides (p < 0.0001). A. lumbricoides-singly stimulated cells had higher IL-4 levels compared to TB plus A. lumbricoides-costimulated Jurkat and THP-1 cells (p < 0.0001). TGF-β levels were also lower in TB-singly stimulated cells compared to TB plus A. lumbricoides-costimulated cells (p < 0.0001). IL-10 levels were lower in TB-stimulated Jurkat and THP-1 cells compared to TB plus A. lumbricoides-costimulated cells (p < 0.0001). Similar results were noted for the human ex vivo study, albeit with a smaller sample size.
CONCLUSIONS: Data suggest that helminths induce a predominant Th2/Treg response which may downregulate critical Th1 responses that are crucial for tuberculosis protection.
摘要：
背景：蠕虫感染在结核病流行地区普遍存在，并与活动性结核病的风险增加有关。与结核分枝杆菌（Mtb）感染引起的促炎Th1反应相反，蠕虫感染诱导抗炎Th2/Treg反应。强大的Th2反应与降低的结核病保护有关。一些研究表明蠕虫感染对BCG疫苗接种和结核病的影响，但机制尚不清楚。
目的：确定结核病和肠道蠕虫合并感染时的细胞因子反应谱。
方法：对于体外研究，用MtbH37Rv和A虫刺激淋巴细胞Jurkat和单核细胞THP-1细胞系（A.lumbricoides）排泄分泌蛋白提取物24小时和48小时。先导人类离体研究由感染Mtb的参与者组成，蠕虫,或者同时感染了Mtb和蠕虫。此后,IFN-γ的基因转录水平，TNF-α,颗粒酶B，穿孔素,IL-2，IL-17，NFATC2，Eomesodermin，未刺激/未感染对照中的IL-4，IL-5，IL-10，TGF-β和FoxP3，使用RT-qPCR确定单个刺激/感染和共刺激/共感染组。
结果：TB刺激的Jurkat细胞具有明显更高水平的IFN-γ，TNF-α,颗粒酶B，和穿孔素与未刺激的对照相比，LPS和A.lumbricoides刺激的细胞，和A.lumbricoides加TB共刺激的细胞(p<0.0001)。IL-2,IL-17,Eomes,在TB刺激的Jurkat细胞中NFATC2水平也较高(p<0.0001)。与用A.lumbricoides单独刺激和用TB加A.lumbricoides共刺激的那些相比,用TB单独刺激的Jurkat和THP-1细胞具有较低的IL-5和IL-4水平(p<0.0001)。与TB加A.lumbricoides共刺激的Jurkat和THP-1细胞相比，A.lumbricoides单刺激的细胞具有更高的IL-4水平（p<0.0001）。与TB加A.lumbricoides共刺激的细胞相比,单独刺激的TB细胞中的TGF-β水平也较低(p<0.0001)。IL-10水平在TB刺激的Jurkat和THP-1细胞中低于TB+A.lumbricoides共刺激的细胞(p<0.0001)。人类离体研究也发现了类似的结果，尽管样本量较小。
结论：数据表明，蠕虫诱导主要的Th2/Treg反应，这可能下调对结核病保护至关重要的关键Th1反应。
目的：确定结核病和肠道蠕虫合并感染时的细胞因子反应谱。
方法：对于体外研究，用MtbH37Rv和A虫刺激淋巴细胞Jurkat和单核细胞THP-1细胞系（A.lumbricoides）排泄分泌蛋白提取物24小时和48小时。先导人类离体研究由感染Mtb的参与者组成，蠕虫,或者同时感染了Mtb和蠕虫。此后,IFN-γ的基因转录水平，TNF-α,颗粒酶B，穿孔素,IL-2，IL-17，NFATC2，Eomesodermin，未刺激/未感染对照中的IL-4，IL-5，IL-10，TGF-β和FoxP3，使用RT-qPCR确定单个刺激/感染和共刺激/共感染组。
结果：TB刺激的Jurkat细胞具有明显更高水平的IFN-γ，TNF-α,颗粒酶B，和穿孔素与未刺激的对照相比，LPS和A.lumbricoides刺激的细胞，和A.lumbricoides加TB共刺激的细胞(p<0.0001)。IL-2,IL-17,Eomes,在TB刺激的Jurkat细胞中NFATC2水平也较高(p<0.0001)。与用A.lumbricoides单独刺激和用TB加A.lumbricoides共刺激的那些相比,用TB单独刺激的Jurkat和THP-1细胞具有较低的IL-5和IL-4水平(p<0.0001)。与TB加A.lumbricoides共刺激的Jurkat和THP-1细胞相比，A.lumbricoides单刺激的细胞具有更高的IL-4水平（p<0.0001）。与TB加A.lumbricoides共刺激的细胞相比,单独刺激的TB细胞中的TGF-β水平也较低(p<0.0001)。IL-10水平在TB刺激的Jurkat和THP-1细胞中低于TB+A.lumbricoides共刺激的细胞(p<0.0001)。人类离体研究也发现了类似的结果，尽管样本量较小。
结论：数据表明，蠕虫诱导主要的Th2/Treg反应，这可能下调对结核病保护至关重要的关键Th1反应。
