Somvanshi Vishal S, Ellis Brian L, Hu Yan, Aroian Raffi V
Section of Cell and Developmental Biology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
Section of Cell and Developmental Biology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
Mol Biochem Parasitol. 2014 Jan;193(1):1-8. doi: 10.1016/j.molbiopara.2013.12.002. Epub 2014 Jan 8.
Intestinal nematodes or roundworms (aka soil-transmitted helminths or STHs) cause great disease. They infect upwards of two billion people, leading to high morbidity and a range of health problems, especially in infected children and pregnant women. Development of resistance to the two main classes of drugs used to treat intestinal nematode infections of humans has been reported. To fight STH infections, we need new and more effective drugs and ways to improve the efficacy of the old drugs. One promising alternative drug is nitazoxanide (NTZ). NTZ, approved for treating human protozoan infections, was serendipitously shown to have therapeutic activity against STHs. However, its mechanism of action against nematodes is not known. Using the laboratory nematode Caenorhabditis elegans, we show that NTZ acts on the nematodes through avr-14, an alpha-type subunit of a glutamate-gated chloride ion channel known for its role in ivermectin susceptibility. In addition, a forward genetic screen to select C. elegans mutants resistant to NTZ resulted in isolation of two NTZ resistant mutants that are not in avr-14, suggesting that additional mechanisms are involved in resistance to NTZ. We found that NTZ combines synergistically with other classes of anthelmintic drugs, i.e. albendazole and pyrantel, making it a good candidate for further studies on its use in drug combination therapy of STH infections. Given NTZ acts against a wide range of nematode parasites, our findings also validate avr-14 as an excellent target for pan-STH therapy.
肠道线虫或蛔虫（又称土壤传播的蠕虫或STH）会引发严重疾病。它们感染了超过20亿人，导致高发病率和一系列健康问题，尤其是在受感染的儿童和孕妇中。据报道，用于治疗人类肠道线虫感染的两类主要药物已出现耐药性。为了对抗STH感染，我们需要新的、更有效的药物以及提高旧药疗效的方法。一种有前景的替代药物是硝唑尼特（NTZ）。已获批准用于治疗人类原生动物感染的NTZ，意外地显示出对STH有治疗活性。然而，其对线虫的作用机制尚不清楚。利用实验室线虫秀丽隐杆线虫，我们发现NTZ通过avr-14作用于线虫，avr-14是一种谷氨酸门控氯离子通道的α亚基，因其在伊维菌素敏感性方面的作用而闻名。此外，通过正向遗传筛选来选择对NTZ耐药的秀丽隐杆线虫突变体，结果分离出两个不在avr-14基因上的NTZ耐药突变体，这表明对NTZ的耐药性还涉及其他机制。我们发现NTZ与其他类别的驱虫药（即阿苯达唑和噻嘧啶）具有协同作用，这使其成为进一步研究其在STH感染联合药物治疗中应用的良好候选药物。鉴于NTZ对多种线虫寄生虫都有作用，我们的研究结果也验证了avr-14作为泛STH治疗的优良靶点。
