Parasite Drug Susceptibility in The Response To Anti-Leishmanial Treatment

总结 拉丁美洲皮肤利什曼病（CL）的总体治疗失败率估计为24%。的 利什曼原虫的药物敏感性和治疗反应之间的关系是不确定的所有形式的 人类利什曼病治疗结果的方法差异和多因素基础 混淆将药物敏感性与临床反应相关联的尝试，并阻碍药物的使用 在治疗政策或决定控制和管理利什曼病的易感性。全面 分析细菌和真菌对不同抗菌药物的敏感性， 治疗结果的敏感性测试表明，宿主因素影响与 治疗的结果。然而，抗菌药物敏感性分析的总体经验表明， 一致表明，在感染耐药的个体中， 生物体之间的关系被称为“90-60规则”。我们将应用抗菌的教训和原则 和抗真菌药物敏感性评估，以确定寄生虫对抗真菌药物敏感性的关系， 利什曼原虫药物与标准治疗的临床和寄生虫学反应， 确定这种关系的寄生虫因素。为实现这一目标，将努力实现三个具体目标： 1.明确临床菌株的体外和离体药物敏感表型之间的关系， CL患者对治疗的临床和寄生虫学反应， 2.确定药物敏感性表型对先天性 免疫/炎症反应及其与治疗结果的关系，以及 3.利什曼原虫药物敏感表型及治疗相关遗传标记的鉴定 结果 我们将战略性地利用广泛收集的利什曼原虫菌株和相应的临床数据库 可从参加过既往完成的随机临床试验的患者和 通过主动病例检测在项目1中前瞻性识别。这些临床菌株对 锑酸葡甲胺和米替福新的临床相关浓度将在 接近体内细胞环境和混杂因素的新型体外和离体分析系统 在评价与治疗结局的关系时，将控制临床应答。遗传标记 治疗结果的潜在机制将通过全基因组SNP分析来确定， 来自治疗反应性和非治疗反应性利什曼原虫的药物敏感性和耐药性利什曼原虫的转录组 响应CL。该项目的结果将确定耐药性在治疗失败中的作用， 指导当前治疗的优化，开发更有效的治疗方法，并为治疗政策提供信息。

SUMMARY Overall treatment failure for cutaneous leishmaniasis (CL) in Latin America is estimated at 24%. The relationship between drug susceptibility of Leishmania and therapeutic response is uncertain for all forms of human leishmaniasis. Methodological disparities and the multifactorial basis of the outcome of treatment confound attempts to correlate drug susceptibility with clinical response and impede the use of drug susceptibility in treatment policy or decisions for control and management of leishmaniasis. Comprehensive analysis of bacterial and fungal susceptibility to diverse antimicrobial drugs and the predictive utility of susceptibility testing for therapeutic outcome has shown that host factors influence the correlation with outcome of treatment. Nevertheless, overall experience in the analyses of antimicrobial drug susceptibility has consistently shown that therapeutic response is significantly lower among individuals infected with resistant organisms in a relation referred to as the “90-60 rule”. We will apply the lessons and principles of antibacterial and antifungal susceptibility assessment, to determine the relationship of parasite susceptibility to anti- leishmanial drugs with the clinical and parasitological response to standard-of-care treatment and identify parasite factors defining this relationship. To achieve this goal three specific aims will be pursued: 1. Define the relationship between in vitro and ex vivo drug susceptibility phenotype of clinical strains and the clinical and parasitological response to treatment in CL patients, 2. Determine the reciprocal effect of drug susceptibility phenotype on activation of innate immune/inflammatory responses and its relationship with outcome of treatment, and 3. Identify genetic markers of Leishmania associated with drug susceptibility phenotype and therapeutic outcome We will strategically exploit an extensive collection of Leishmania strains and corresponding clinical data base available from patients who have participated in previously concluded randomized clinical trials, and patients prospectively identified in Project 1 through active case detection. Susceptibility of these clinical strains to pharmacologically relevant concentrations of meglumine antimoniate and miltefosine will be determined in novel in vitro and ex vivo analytical systems that approximate the in vivo cellular environment and confounders of clinical response will be controlled in evaluating the relationship with treatment outcome. Genetic markers and underlying mechanisms of therapeutic outcome will be identified by SNP profiling from genome-wide transcriptomes of drug-susceptible and resistant Leishmania from therapeutically responsive and non- responsive CL. Results of this project will establish the contribution of drug resistance in treatment failure, guide optimization of current treatment, development of more effective treatments, and inform treatment policy.