Drug-induced exposure of Schistosoma mansoni antigens SmCD59a and SmKK7.
Drug-induced exposure of Schistosoma mansoni antigens SmCD59a and SmKK7.
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DOI：
10.1371/journal.pntd.0003593
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发表时间：
2015-03
影响因子：
3.8
通讯作者：
Schramm G
中科院分区：
文献类型：
--
作者：
Reimers N;Homann A;Höschler B;Langhans K;Wilson RA;Pierrot C;Khalife J;Grevelding CG;Chalmers IW;Yazdanbakhsh M;Hoffmann KF;Hokke CH;Haas H;Schramm G
血吸虫病是一个严重的健康问题，特别是在发展中国家，影响到2.43亿多人。到目前为止，只有少数几种驱虫药可用。药物治疗的一个主要障碍是蠕虫发育过程中的不同发育阶段和不同的宿主隔室。驱虫药主要在成虫或新鲜转化的尾蚴上进行试验。缺乏有关幼虫阶段的知识。在这项研究中，我们使用体外培养的童虫（年龄在2至14天之间），以探讨三种驱虫药吡喹酮，蒿甲醚，奥曲喹的药物作用。此外，我们分析了药物治疗前后两种示例性染色体抗原SmCD59a和SmKK 7的抗体可及性。我们的结果表明，吡喹酮在1 μM的浓度下应用抑制所有生命阶段的发育。应用10 μM吡喹酮可导致所有童虫的形态发生显著变化。蒿甲醚在1和10 μM时具有不同的作用，这取决于是否将其应用于2天与7天和14天的囊胚期。虽然2日龄的胚泡未被杀死，但进一步发育受到抑制，但在7日龄和14日龄的胚泡中观察到严重的形态学损伤。羟喹（1和10 μM）导致所有生命阶段的严重形态学损伤。分析药物治疗前抗原SmCD59a和SmKK7的可及性，显示在活的完整童虫上没有抗体结合。然而，当用驱虫剂处理童虫时，两种抗原都暴露在幼虫上。结果表明，羟喹在促进抗体与所有发育阶段的囊胚结合方面最有效。这项研究揭示了驱虫药对幼虫作用的显著差异。药物治疗增加了表面抗原呈递，使幼虫易于受到抗体攻击。血吸虫病是发展中国家的主要寄生虫病之一，每年仍造成20万人死亡。目前，在撒哈拉以南非洲地区正在开展吡喹酮（治疗血吸虫病的首选药物）的大规模药物管理方案。吡喹酮虽然对蠕虫有效，但不能治愈早期感染。染色体的复杂发育阶段和通过具有不同局部药物浓度的不同宿主隔室的迁移是药物治疗的挑战。在感染哺乳动物宿主后，童虫穿过皮肤和肺、肝和肠的脉管系统。在迁徙过程中，它们在大约4至5周内从幼虫发育成成对的成虫。到目前为止，仅在蠕虫或新鲜转化的童虫上分析了药物作用。缺乏关于对幼虫阶段影响的信息。我们能够将前三周的幼虫发育转移到培养皿中。该工具可用于分析药物对童虫的作用，并用于研究抗原的可及性、表达和定位。药物活性的一个重要方面是通过增加抗原呈递使寄生虫的幼虫对宿主的免疫系统脆弱。我们证明在体外培养的曼氏血吸虫幼虫，SmCD59a和SmKK7，作为隐藏的抗原的例子，成为药物治疗后获得抗体。
Schistosomiasis is a serious health problem especially in developing countries and affects more than 243 million people. Only few anthelmintic drugs are available up to now. A major obstacle for drug treatment is the different developmental stages and the varying host compartments during worm development. Anthelmintic drugs have been tested mainly on adult schistosomes or freshly transformed cercariae. Knowledge concerning the larval stages is lacking. In this study, we used in vitro-grown schistosomula (aged between 2 to 14 days) to investigate drug effects of the three anthelmintics praziquantel, artemether, and oxamniquine. Further, we analyzed the antibody accessibility of two exemplary schistosome antigens SmCD59a and SmKK7, before and after drug treatment. Our results demonstrated that praziquantel applied at a concentration of 1 μM inhibited development of all life stages. Application of 10 μM praziquantel led to dramatic morphological changes of all schistosomula. Artemether at 1 and 10 μM had differential effects depending on whether it was applied to 2-day as compared to 7- and 14-day schistosomula. While 2-day schistosomula were not killed but inhibited from further development, severe morphological damage was seen in 7- and 14-day schistosomula. Oxamniquine (1 and 10 μM) led to severe morphological impairment in all life stages. Analyzing the accessibility of the antigens SmCD59a and SmKK7 before drug treatment showed no antibody binding on living intact schistosomula. However, when schistosomula were treated with anthelmintics, both antigens became exposed on the larvae. Oxamniquine turned out to be most effective in promoting antibody binding to all schistosomula stages. This study has revealed marked differences in anthelmintic drug effects against larvae. Drug treatment increases surface antigen presentation and renders larvae accessible to antibody attack. Schistosomiasis is one of the major parasitic diseases in developing countries and still causes 200,000 deaths per year. Mass drug administration programs with praziquantel, the drug of choice against schistosomiasis, are currently undertaken in Sub-Saharan Africa. Praziquantel, although efficient against adult worms, fails to cure early infection. The complex developmental stages of schistosomes and migration through varying host compartments with different local drug concentration are a challenge for drug treatment. After infecting their mammalian host, schistosomula traverse through skin and the vasculature of lung, liver and intestines. During their migration, they develop from larvae to paired adults in approximately 4 to 5 weeks. So far, drug effects have been analyzed on adult worms or freshly transformed schistosomula only. Information about the effects on the larval stages is lacking. We were able to transfer the larval development of the first three weeks into the culture dish. This tool can be used for the analysis of drug effects against schistosomula and for investigation of the accessibility, expression and localization of antigens. Rendering the parasite’s larvae vulnerable to the host’s immune system by increasing antigen presentation is an important aspect of drug activity. We demonstrate on in vitro-cultured Schistosoma mansoni larvae, that SmCD59a and SmKK7, as examples for hidden antigens, become accessible to antibodies following drug treatment.
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DOI：
10.1016/j.ijpddr.2014.07.005
发表时间：
2014-12
影响因子：
4
作者：
Beckmann, Svenja;Long, Thavy;Scheld, Christina;Geyer, Rudolf;Caffrey, Conor R.;Grevelding, Christoph G.
通讯作者：
Grevelding, Christoph G.
影响因子：
5.2
作者：
Keiser, Jennifer;Manneck, Theresia;Vargas, Mireille
通讯作者：
Vargas, Mireille
DOI：
10.4269/ajtmh.2004.71.774
发表时间：
2004-12-01
影响因子：
3.3
作者：
Bergquist, R;Utzinger, J;Tanner, M
通讯作者：
Tanner, M
影响因子：
3.8
作者：
Farias LP;Krautz-Peterson G;Tararam CA;Araujo-Montoya BO;Fraga TR;Rofatto HK;Silva FP Jr;Isaac L;Da'dara AA;Wilson RA;Shoemaker CB;Leite LC
通讯作者：
Leite LC
影响因子：
2.2
作者：
FALLON, PG;SMITH, P;DOENHOFF, MJ
通讯作者：
DOENHOFF, MJ