Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, United Kingdom.
Infynity Biomarkers, Lyon, France.
PLoS Negl Trop Dis. 2022 Oct 3;16(10):e0010827. doi: 10.1371/journal.pntd.0010827. eCollection 2022 Oct.
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and is a serious public health problem throughout Latin America. With 6 million people infected, there is a major international effort to develop new drugs. In the chronic phase of the disease, the parasite burden is extremely low, infections are highly focal at a tissue/organ level, and bloodstream parasites are only intermittently detectable. As a result, clinical trials are constrained by difficulties associated with determining parasitological cure. Even highly sensitive PCR methodologies can be unreliable, with a tendency to produce "false-cure" readouts. Improved diagnostic techniques and biomarkers for cure are therefore an important medical need.
METHODOLOGY/PRINCIPAL FINDINGS: Using an experimental mouse model, we have combined a multiplex assay system and highly sensitive bioluminescence imaging to evaluate serological procedures for diagnosis of T. cruzi infections and confirmation of parasitological cure. We identified a set of three antigens that in the context of the multiplex serology system, provide a rapid, reactive and highly accurate read-out of both acute and chronic T. cruzi infection. In addition, we describe specific antibody responses where down-regulation can be correlated with benznidazole-mediated parasite reduction and others where upregulation is associated with persistent infection. One specific antibody (IBAG39) highly correlated with the bioluminescence flux and represents a promising therapy monitoring biomarker in mice.
CONCLUSIONS/SIGNIFICANCE: Robust, high-throughput methodologies for monitoring the efficacy of anti-T. cruzi drug treatment are urgently required. Using our experimental systems, we have identified markers of infection or parasite reduction that merit assessing in a clinical setting for the longitudinal monitoring of drug-treated patients.
恰加斯病由原生动物寄生虫克氏锥虫引起，是拉丁美洲的一个严重公共卫生问题。受感染人数达 600 万，国际社会正在大力开发新药。在疾病的慢性期，寄生虫负担极低，感染高度局限于组织/器官水平，且血流寄生虫只能间歇性检测到。因此，临床试验受到确定寄生虫治愈的相关困难的限制。即使是高度敏感的 PCR 方法也可能不可靠，存在产生“假治愈”读数的倾向。因此，改进的诊断技术和治愈生物标志物是重要的医疗需求。
方法/主要发现：我们使用实验小鼠模型，结合多重分析系统和高灵敏度生物发光成像，评估了用于诊断 T. cruzi 感染和确认寄生虫治愈的血清学程序。我们确定了一组三种抗原，在多重血清学系统的背景下，提供了对急性和慢性 T. cruzi 感染的快速、反应性和高度准确的读数。此外，我们描述了特定的抗体反应，其中下调可以与苯并咪唑介导的寄生虫减少相关，而其他上调与持续感染相关。一种特定的抗体（IBAG39）与生物发光通量高度相关，是一种有前途的小鼠治疗监测生物标志物。
结论/意义：迫切需要用于监测抗 T. cruzi 药物治疗效果的强大、高通量方法。使用我们的实验系统，我们已经确定了感染或寄生虫减少的标志物，值得在临床环境中进行评估，以对接受药物治疗的患者进行纵向监测。
