Assessing treatment with miltefosine as an intervention strategy for visceral leishmaniasis in Brazil

利什曼病是一种严重的人类疾病，也是世界上最被忽视的疾病之一，主要影响发展中国家的穷人。3.5亿人面临感染这种疾病的风险，它在健康和经济方面都造成了严重的代价，并耗尽了本可用于促进发展中国家增长的资源。目前还没有针对这种疾病的有效疫苗，化疗是减轻利什曼病负担的主要手段。内脏利什曼病(VL)是最严重的利什曼病形式，每年在巴西有6000例记录；它由婴儿利什曼原虫引起，并通过沙蝇传播。不幸的是，可用于治疗VL的药物有许多局限性，新的药物，或者说迫切需要使用目前获得许可的药物的新方法。米替福辛就是这样一种药物，它曾在印度成功地用于治疗VL，但在2006年在巴西的一次临床试验中并未如此成功。我们最近的研究表明，婴儿乳杆菌基因组的一个特定部分(称为MSL)在一些巴西寄生虫菌株中丢失，从而使它们对药物米替福辛不那么敏感。我们基金会项目的目的是确定MSL在巴西发现的寄生虫种群中的流行程度。为此，我们将使用聚合酶链式反应验证基因诊断测试，并对从巴西比奥伊州患者分离的查加西乳杆菌寄生虫的基因组进行测序。如果发现MSL经常存在，那么可以进行一项新的临床试验，携带MSL寄生虫的利什曼病患者将接受米替福辛治疗，而那些寄生虫不含MSL的利什曼病患者将使用目前的药物治疗。我们将对利什曼原虫基因中的MSL基因进行基因操作，以找出为什么MSL赋予米替福辛敏感性。我们还将通过测试在当地巴西树木中发现的一种天然产品是否会在沙蝇媒介中选择寄生虫来调查为什么MSL在L.infantum中丢失。总体而言，我们预计这项研究的结果将大大改善对寄生虫生活环境如何影响其对药物的敏感性以及耐药的分子机制的理解。

Leishmaniasis is a severe disease of humans and one of the world's most neglected diseases, primarily affecting the poor in developing countries. 350 million people are at risk of contracting the disease and it has severe costs in both health and economic terms and drains resources that could be used to promote growth of developing nations. There is no effective vaccine against the disease and chemotherapy is the prime means for reducing the leishmaniasis burden. Visceral Leishmaniasis (VL) is the most severe form of leishmaniasis with 6,000 cases recorded in Brazil each year; it is caused by Leishmania infantum and transmitted by sandflies. Unfortunately the drugs available to treat VL have many limitations and new drugs, or new ways of using currently licensed drugs are desperately needed. One such drug is miltefosine, which has been used successfully to treat VL in India, but which was not so successful in a clinical trial in Brazil in 2006. Our recent research suggests that a specific section of the L. infantum genome (termed the MSL) is lost in some Brazilian strains of the parasite making them less susceptible to the drug miltefosine. The aim of our foundation project is to determine how prevalent the MSL is in the population of parasites that are found in Brazil. To do this we will validate a genetic diagnostic test using PCR, as well as sequence the genomes of L. chagasi parasites isolated from patients in the State of Piaui in Brazil. If the MSL is found to be present often, then a new clinical trial could be run, where leishmaniasis patients with parasites containing the MSL would be treated with miltefosine, whilst those leishmaniasis patients with parasites that do not contain the MSL would be treated using current drugs. We will genetically manipulate the MSL genes in Leishmania genes to find out why the MSL confers sensitivity to miltefosine. We shall also investigate why the MSL is lost in L. infantum, by testing if a natural product found in local Brazilian trees causes selection of parasites whilst in the sandfly vector. Overall, we expect the outcome from this study to be a greatly improved understanding of how the environment in which the parasite lives influences its susceptibility to drugs and the molecular mechanisms of drug resistance.