Parasite Drug Susceptibility in The Response To Anti-Leishmanial Treatment

摘要 在拉丁美洲，皮肤利什曼病(CL)的总体治疗失败率估计为24%。这个 利什曼病的药物敏感性和治疗反应之间的关系对于所有形式的利什曼病都是不确定的 人类利什曼病。治疗结果的方法学差异和多因素基础 将药物敏感性与临床反应联系起来并阻碍药物使用的混淆尝试 在治疗政策或控制和管理利什曼病的决策中的敏感性。全面 细菌和真菌对多种抗菌药物的敏感性分析及其预测价值 对治疗结果的敏感性测试表明，宿主因素影响与 治疗结果。尽管如此，抗菌药物敏感性分析的总体经验是 一贯表明，在感染耐药病毒的个体中，治疗反应明显较低。 生物在一种被称为“90-60法则”的关系中。我们将应用抗菌的经验教训和原则 和抗真菌药物敏感性评估，以确定寄生虫敏感性与抗真菌药物的关系 利什曼病药物与临床和寄生虫学反应的标准治疗和识别 寄生因素决定了这种关系。为实现这一目标，将实现三个具体目标： 1.明确临床菌株体外和体外药敏表型与 慢性萎缩性胃炎患者的临床和寄生虫学反应， 2.确定药物敏感性表型对先天活化的交互作用 免疫/炎症反应及其与治疗结果的关系 3.寻找与药物敏感性表型和治疗相关的利什曼病遗传标记 结果 我们将有策略地开发广泛收集的利什曼原虫菌株和相应的临床数据库 可从参与过先前总结的随机临床试验的患者和患者获得 通过正在进行的病例检测，预期在项目1中确定。这些临床分离株对沙门氏菌的敏感性 药物上相关浓度的锑酸葡甲胺和米替福辛将在#年进行测定。 接近体内细胞环境和混杂因素的新的体外和体外分析系统 在评价与治疗结果的关系时，将控制临床反应的好坏。遗传标记 治疗结果的潜在机制将通过基因组范围内的SNP图谱来确定 药物敏感和耐药利什曼原虫的治疗反应性和非反应性转录本 响应性CL。该项目的结果将确定耐药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，并告知治疗政策。

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.