Distinct antibody responses of patients with mild and severe leptospirosis determined by whole proteome microarray analysis.
Distinct antibody responses of patients with mild and severe leptospirosis determined by whole proteome microarray analysis.
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DOI：
10.1371/journal.pntd.0005349
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发表时间：
2017-01
影响因子：
3.8
通讯作者：
Felgner PL
中科院分区：
文献类型：
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作者：
Lessa-Aquino C;Lindow JC;Randall A;Wunder E;Pablo J;Nakajima R;Jasinskas A;Cruz JS;Damião AO;Nery N;Ribeiro GS;Costa F;Hagan JE;Reis MG;Ko AI;Medeiros MA;Felgner PL
钩端螺旋体病是一种重要的人畜共患病。人类通常表现为轻度非特异性发热性疾病，但其中一部分会发展为更严重的结局，如多器官衰竭，肺出血和死亡。这种并发症被认为取决于几个因素，包括宿主免疫力。保护性免疫与体液免疫反应有关，但对自然获得性钩端螺旋体感染过程中产生的免疫反应知之甚少。在这里，我们使用蛋白质微阵列芯片，以描绘抗体反应的严重和轻度钩端螺旋体病患者对完整的问号血清型Copenhageni预测ORFeome。我们发现了数量有限的免疫显性抗原，有36个抗原特异性的患者，其中11个是潜在的血清学诊断抗原，确定在急性期，和33个潜在的亚单位疫苗的目标，恢复后检测。此外，我们在具有不同临床结果的患者中发现了不同的抗体谱：在重度组中，总体IgM应答没有变化，IgG应答随时间增加，而IgM和IgG应答在轻度患者组中保持稳定。对个体患者反应的分析显示，与轻度组中29%的患者相比，重度组中>74%的患者随时间推移IgG显著增加。此外，在轻度组中，90%的IgM应答没有随时间变化，而在重度组中，这一比例为51%。在本研究中，我们检测了与疾病严重程度相关的抗体谱，并推测轻度疾病患者由于预先存在的抗体而免受严重后果的影响，而重度钩端螺旋体病患者则表现出首次暴露的典型抗体谱。我们的研究结果代表了对钩端螺旋体感染的体液免疫应答的理解的重大进展，并且我们已经确定了开发亚单位疫苗和诊断测试的新目标。钩端螺旋体病是一种具有全球重要性的人畜共患疾病，每年有超过100万例病例和近60，000例死亡。症状性疾病表现的范围从具有非特异性症状的轻度发热性疾病到以多器官衰竭、肺出血和死亡为特征的严重形式。导致严重后果的因素尚不清楚，但宿主免疫反应可能起着重要作用。在本研究中，我们应用高通量技术，以确定严重和轻度钩端螺旋体病患者的抗体谱。我们发现了有限数量的免疫显性抗原，特异于患者。令人惊讶的是，我们发现抗体库在具有不同临床结果的患者中变化，并假设具有轻度症状的患者由于预先存在的抗体而免受严重疾病的影响，而具有严重结果的患者的特征代表首次暴露。这些发现代表了对钩端螺旋体感染的体液免疫应答的认识向前迈出了实质性的一步，我们已经确定了疫苗和诊断测试开发的新靶点。
Leptospirosis is an important zoonotic disease worldwide. Humans usually present a mild non-specific febrile illness, but a proportion of them develop more severe outcomes, such as multi-organ failure, lung hemorrhage and death. Such complications are thought to depend on several factors, including the host immunity. Protective immunity is associated with humoral immune response, but little is known about the immune response mounted during naturally-acquired Leptospira infection. Here, we used protein microarray chip to profile the antibody responses of patients with severe and mild leptospirosis against the complete Leptospira interrogans serovar Copenhageni predicted ORFeome. We discovered a limited number of immunodominant antigens, with 36 antigens specific to patients, of which 11 were potential serodiagnostic antigens, identified at acute phase, and 33 were potential subunit vaccine targets, detected after recovery. Moreover, we found distinct antibody profiles in patients with different clinical outcomes: in the severe group, overall IgM responses do not change and IgG responses increase over time, while both IgM and IgG responses remain stable in the mild patient group. Analyses of individual patients’ responses showed that >74% of patients in the severe group had significant IgG increases over time compared to 29% of patients in the mild group. Additionally, 90% of IgM responses did not change over time in the mild group, compared to ~51% in the severe group. In the present study, we detected antibody profiles associated with disease severity and speculate that patients with mild disease were protected from severe outcomes due to pre-existing antibodies, while patients with severe leptospirosis demonstrated an antibody profile typical of first exposure. Our findings represent a significant advance in the understanding of the humoral immune response to Leptospira infection, and we have identified new targets for the development of subunit vaccines and diagnostic tests. Leptospirosis is zoonotic disease of global importance, with over a million cases and nearly 60,000 deaths annually. Symptomatic disease presentation ranges from a mild febrile disease with non-specific symptoms to severe forms, characterized by multi-organ failure, lung hemorrhage, and death. Factors driving severe outcomes remain unclear, but the host immune response likely plays an important role. In the present study, we applied high throughput techniques to identify the antibody profiles of patients with severe and mild leptospirosis. We discovered a limited number of immunodominant antigens, specific to patients. Surprisingly, we found the antibody repertoire varies in patients with different clinical outcomes and hypothesized that patients with mild symptoms were protected from severe disease due to pre-existing antibodies, while the profile of patients with severe outcomes was representative of a first exposure. These findings represent a substantial step forward in the knowledge of the humoral immune response to Leptospira infection, and we have identified new targets for vaccine and diagnostic test development.