Histamine 1 Receptor Blockade Enhances Eosinophil-Mediated Clearance of Adult Filarial Worms.
Histamine 1 Receptor Blockade Enhances Eosinophil-Mediated Clearance of Adult Filarial Worms.
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DOI：
10.1371/journal.pntd.0003932
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发表时间：
2015
影响因子：
3.8
通讯作者：
Mitre E
中科院分区：
文献类型：
--
作者：
Fox EM;Morris CP;Hübner MP;Mitre E
丝虫是一种组织侵入性线虫，可引起象皮病和河盲症等疾病。本研究的目的是表征组胺在感染的BALB/c小鼠，丝虫病的小鼠模型的Litomosoides sigmodontis的作用。时间进程的研究表明，虽然组氨酸脱羧酶mRNA的表达增加，在整个12周的感染，血清组胺水平表现出两个高峰，一个30分钟后，原发性感染和8周后。有趣的是，与未治疗的感染对照组相比，用组胺受体1抑制剂非索非那定治疗的小鼠在感染小鼠中表现出显著降低的蠕虫负担。尽管非索非那定治疗的小鼠具有降低的抗原特异性IgE水平以及较低的脾细胞IL-5和IFN γ产生，但它们在成年L. sigmodontis蠕虫居住。非索非那定介导的L. sigmodontis蠕虫依赖于宿主嗜酸性粒细胞，因为非索非那定不能降低嗜酸性粒细胞缺陷型dblGATA小鼠的蠕虫负荷。这些研究结果表明，组胺释放引起的组织侵入蠕虫可能有助于寄生虫的生存减少嗜酸性反应。此外，这些结果提高了H1受体抑制剂与目前的驱虫剂相结合可能会提高丝虫和其他组织侵入性蠕虫的治疗效果的可能性。丝虫是一种组织侵入性寄生蛔虫，在全世界感染超过1亿人，并导致河盲症和象皮病等使人衰弱的疾病。限制我们消除这些感染的能力的主要因素之一是缺乏短期治疗时杀死成虫的药物。此外，成虫从受感染个体中清除的机制仍然知之甚少。在这项研究中，我们证明，非索非那定，组胺受体1的抑制剂，通过依赖于宿主嗜酸性粒细胞的机制显着减少成虫数量的感染小鼠的治疗。这些研究结果表明，组胺释放引起的寄生虫可能会帮助寄生虫生存减少嗜酸性反应。此外，由于抗组胺药通常是安全的药物，这些结果提高了抗组胺药单独使用或与其他抗丝虫药物如乙胺嗪（DEC）联合使用的可能性，以消除感染个体的丝虫成虫。
Filariae are tissue-invasive nematodes that cause diseases such as elephantiasis and river blindness. The goal of this study was to characterize the role of histamine during Litomosoides sigmodontis infection of BALB/c mice, a murine model of filariasis. Time course studies demonstrated that while expression of histidine decarboxylase mRNA increases throughout 12 weeks of infection, serum levels of histamine exhibit two peaks—one 30 minutes after primary infection and one 8 weeks later. Interestingly, mice treated with fexofenadine, a histamine receptor 1 inhibitor, demonstrated significantly reduced worm burden in infected mice compared to untreated infected controls. Although fexofenadine-treated mice had decreased antigen-specific IgE levels as well as lower splenocyte IL-5 and IFNγ production, they exhibited a greater than fourfold rise in eosinophil numbers at the tissue site where adult L. sigmodontis worms reside. Fexofenadine-mediated clearance of L. sigmodontis worms was dependent on host eosinophils, as fexofenadine did not decrease worm burdens in eosinophil-deficient dblGATA mice. These findings suggest that histamine release induced by tissue invasive helminths may aid parasite survival by diminishing eosinophilic responses. Further, these results raise the possibility that combining H1 receptor inhibitors with current anthelmintics may improve treatment efficacy for filariae and other tissue-invasive helminths. Filariae are tissue-invasive parasitic roundworms that infect over 100 million people worldwide and cause debilitating conditions such as river blindness and elephantiasis. One of the major factors limiting our ability to eliminate these infections is the lack of drugs that kill adult worms when given as a short course therapy. Additionally, the mechanisms by which adult worms are cleared from infected individuals remains poorly understood. In this study, we demonstrate that treatment of infected mice with fexofenadine, an inhibitor of histamine receptor 1, significantly reduces adult worm numbers through a mechanism dependent on host eosinophils. These findings suggest that histamine release induced by parasitic worms may aid parasite survival by decreasing eosinophilic responses. Further, as antihistamines are generally safe medications, these results raise the possibility that antihistamine therapy may be useful either alone, or potentially in combination with other antifilarial medications such as diethylcarbamazine (DEC), to eliminate adult filarial worms from infected individuals.