PDF(Pubmed)
Abstract：
A Mycobacterium ulcerans human challenge model has the potential to fundamentally advance our understanding of early human immune responses to infection, while rapidly evaluating vaccines and other therapeutic interventions. Here, using a murine tail infection model, we tested a very well-characterized working cell bank of the proposed challenge isolate M. ulcerans JKD8049 in naïve and Mycobacterium bovis bacille Calmette-Guérin (BCG)-vaccinated BALB/c mice. All 10 naïve mice were successfully infected with 20 colony-forming units (CFU) of M. ulcerans [95% confidence interval (CI) 17-22 CFU] with a mean time to visible lesion of 86 days (95% CI 79-92 days). In the 10 vaccinated mice, there was a significant delay in the mean time to lesion compared to the naïve controls of 24 days (P = 0.0003), but all mice eventually developed ulcerative lesions. This study informs a future human infection model by demonstrating the successful application of the challenge agent in this in vivo model and highlights both the promise and the problems with trying to induce protective immunity against M. ulcerans.
OBJECTIVE: In preparation for its proposed use in a controlled human infection model (CHIM), this study reports the successful infection of BALB/c mice using a carefully characterized, low-dose inoculum of Mycobacterium ulcerans JKD8049 (our proposed CHIM strain). We also demonstrate that Mycobacterium bovis bacille Calmette-Guérin delays the onset of disease but cannot alter the course of illness once a lesion becomes apparent. We also validate the findings of previous low-dose challenges that used less accurate methods to determine the inoculum, but our presented methodology is practical, accurate, and anticipated to be reproducible.
OBJECTIVE: In preparation for its proposed use in a controlled human infection model (CHIM), this study reports the successful infection of BALB/c mice using a carefully characterized, low-dose inoculum of Mycobacterium ulcerans JKD8049 (our proposed CHIM strain). We also demonstrate that Mycobacterium bovis bacille Calmette-Guérin delays the onset of disease but cannot alter the course of illness once a lesion becomes apparent. We also validate the findings of previous low-dose challenges that used less accurate methods to determine the inoculum, but our presented methodology is practical, accurate, and anticipated to be reproducible.
摘要：
溃疡分枝杆菌人类挑战模型有可能从根本上推进我们对早期人类感染免疫反应的理解，同时快速评估疫苗和其他治疗干预措施。这里,使用鼠尾感染模型，我们在未接种和牛分枝杆菌Calmette-Guérin（BCG）接种的BALB/c小鼠中测试了拟议的攻击分离株溃疡分枝杆菌JKD8049的特征非常明确的工作细胞库。所有10只幼稚小鼠均成功感染20个菌落形成单位(CFU)的溃疡分枝杆菌[95%置信区间(CI)17-22CFU],平均至可见病变的时间为86天(95%CI79-92天)。在10只接种疫苗的小鼠中，与24天的初始对照组相比，平均病变时间显着延迟（P=0.0003），但所有小鼠最终都出现了溃疡性病变.该研究通过证明攻击剂在该体内模型中的成功应用为未来的人类感染模型提供了信息，并强调了尝试诱导针对溃疡分枝杆菌的保护性免疫的前景和问题。
目的：在准备其在受控人类感染模型（CHIM）中的拟议用途时，这项研究报告了BALB/c小鼠的成功感染，溃疡分枝杆菌JKD8049（我们提出的CHIM菌株）的低剂量接种物。我们还证明，牛分枝杆菌Calmette-Guérin会延迟疾病的发作，但一旦病变变得明显，就无法改变病程。我们还验证了以前使用不太准确的方法来确定接种物的低剂量挑战的结果，但是我们提出的方法是实用的，准确,并有望重现。
目的：在准备其在受控人类感染模型（CHIM）中的拟议用途时，这项研究报告了BALB/c小鼠的成功感染，溃疡分枝杆菌JKD8049（我们提出的CHIM菌株）的低剂量接种物。我们还证明，牛分枝杆菌Calmette-Guérin会延迟疾病的发作，但一旦病变变得明显，就无法改变病程。我们还验证了以前使用不太准确的方法来确定接种物的低剂量挑战的结果，但是我们提出的方法是实用的，准确,并有望重现。
