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

评估米替福辛治疗作为巴西内脏利什曼病的干预策略

• 批准号: MR/P024483/1
• 负责人: Jeremy Mottram
• 金额: $ 70.93万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP024483%2F1
• 关键词: Assessing; treatment; miltefosine; intervention; strategy

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.

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，并消耗了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，巴西每年记录有6000例；它是由幼年利什曼原虫引起的，并通过白蛉传播。不幸的是，可用于治疗VL的药物有许多局限性，迫切需要新的药物，或者使用现有许可药物的新方法。其中一种药物是米特福辛，它在印度成功地用于治疗VL，但在2006年巴西的临床试验中却不太成功。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，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，我们将利用聚合酶链反应验证一种基因诊断测试，并对从巴西皮奥伊州患者身上分离的查加西L.寄生虫的基因组进行测序。如果发现MSL经常出现，那么可以进行一项新的临床试验，其中含有MSL的寄生虫的利什曼病患者将用米替福辛治疗，而那些不含MSL的寄生虫的利什曼病患者将使用现有药物治疗。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MSL对米替福辛敏感的原因。我们还将通过测试在巴西当地树木中发现的一种天然产品是否导致寄生虫选择而在白蛉媒介中导致寄生虫选择，来调查MSL在幼年白蛉中消失的原因。总的来说，我们期望这项研究的结果能够大大提高人们对寄生虫生存环境如何影响其对药物的敏感性以及耐药性的分子机制的理解。

项目成果

3'Nucleotidase/nuclease is required for Leishmania infantum clinical isolate susceptibility to miltefosine.

• DOI: 10.1016/j.ebiom.2022.104378
• 发表时间: 2022-12
• 期刊: EBIOMEDICINE
• 影响因子: 11.1
• 作者: Carnielli, Juliana B. T.;Dave, Anuja;Romano, Audrey;Forrester, Sarah;de Faria, Pedro R.;Monti-Rocha, Renata;Costa, Carlos H. N.;Dietze, Reynaldo;Graham, Ian A.;Mottram, Jeremy C.
• 通讯作者: Mottram, Jeremy C.

Natural Resistance of Leishmania infantum to Miltefosine Contributes to the Low Efficacy in the Treatment of Visceral Leishmaniasis in Brazil

• DOI: 10.4269/ajtmh.18-0949
• 发表时间: 2019-01-01
• 期刊: AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE
• 影响因子: 3.3
• 作者: Carnielli, Juliana B. T.;Monti-Rocha, Renata;Dietze, Reynaldo
• 通讯作者: Dietze, Reynaldo

A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis.

• DOI: 10.1016/j.ebiom.2018.09.029
• 发表时间: 2018-10
• 期刊: EBioMedicine
• 影响因子: 11.1
• 作者: Carnielli JBT;Crouch K;Forrester S;Silva VC;Carvalho SFG;Damasceno JD;Brown E;Dickens NJ;Costa DL;Costa CHN;Dietze R;Jeffares DC;Mottram JC
• 通讯作者: Mottram JC