Table_4_Unraveling cross-reactivity of anti-glycan IgG responses in filarial nematode infections.xlsx

Parasitic nematodes responsible for filarial diseases cause chronic disablement in humans worldwide. Elimination programs have substantially reduced the rate of infection in certain areas, but limitations of current diagnostics for population surveillance have been pointed out and improved assays are needed to reach the elimination targets. While serological tests detecting antibodies to parasite antigens are convenient tools, those currently available are compromised by the occurrence of antibodies cross-reactive between nematodes, as well as by the presence of residual antibodies in sera years after treatment and clearance of the infection. We recently characterized the N-linked and glycosphingolipid derived glycans of the parasitic nematode Brugia malayi and revealed the presence of various antigenic structures that triggered immunoglobulin G (IgG) responses in infected individuals. To address the specificity of IgG binding to these glycan antigens, we screened microarrays containing Brugia malayi glycans with plasma from uninfected individuals and from individuals infected with Loa loa, Onchocerca volvulus, Mansonella perstans and Wuchereria bancrofti, four closely related filarial nematodes. IgG to a restricted subset of cross-reactive glycans was observed in infection plasmas from all four species. In plasma from Onchocerca volvulus and Mansonella perstans infected individuals, IgG binding to many more glycans was additionally detected, resulting in total IgG responses similar to the ones of Brugia malayi infected individuals. For these infection groups, Brugia malayi, Onchocerca volvulus and Mansonella perstans, we further studied the different IgG subclasses to Brugia malayi glycans. In all three infections, IgG1 and IgG2 appeared to be the major subclasses involved in response to glycan antigens. Interestingly, in Brugia malayi infected individuals, we observed a marked reduction in particular in IgG2 to parasite glycans post-treatment with anthelminthic, suggesting a promising potential for diagnostic applications. Thus, we compared the IgG response to a broad repertoire of Brugia malayi glycans in individuals infected with various filarial nematodes. We identified broadly cross-reactive and more specific glycan targets, extending the currently scarce knowledge of filarial nematode glycosylation and host anti-glycan antibody response. We believe that our initial findings could be further exploited to develop disease-specific diagnostics as part of an integrated approach for filarial disease control.

引发丝虫病的寄生线虫（parasitic nematodes）在全球范围内造成人类慢性残疾。丝虫病消除项目已在部分地区大幅降低了感染率，但当前用于人群监测的诊断方法存在局限，亟需改进的检测手段以达成消除目标。尽管检测寄生虫抗原抗体的血清学检测是便捷的工具，但现有手段因线虫间抗体交叉反应，以及感染清除后数年血清中仍存在残留抗体而存在缺陷。我们近期对寄生线虫马来布鲁线虫（Brugia malayi）的N连接糖蛋白与糖鞘脂衍生聚糖进行了表征，并揭示了多种可在感染者体内触发免疫球蛋白G（IgG）应答的抗原结构。为探究IgG与这些聚糖抗原的结合特异性，我们使用未感染者以及感染罗阿丝虫（Loa loa）、盘尾丝虫（Onchocerca volvulus）、常现曼森线虫（Mansonella perstans）和班氏吴策线虫（Wuchereria bancrofti）这四种密切相关的丝虫线虫的血浆，对包含马来布鲁线虫聚糖的微阵列进行了筛选。在这四种感染的血浆中，均观察到针对有限交叉反应聚糖子集的IgG结合。而在感染盘尾丝虫与常现曼森线虫的个体血浆中，还检测到更多聚糖的IgG结合，其总IgG应答水平与马来布鲁线虫感染者相近。针对这三组感染（马来布鲁线虫、盘尾丝虫与常现曼森线虫），我们进一步研究了针对马来布鲁线虫聚糖的不同IgG亚类。在这三种感染中，IgG1与IgG2似乎是介导聚糖抗原应答的主要亚类。有趣的是，在感染马来布鲁线虫的个体中，我们观察到接受抗蠕虫治疗后，其针对寄生虫聚糖的IgG，尤其是IgG2水平显著降低，这表明其在诊断应用中具有良好的潜力。因此，我们对比了感染多种丝虫线虫的个体对广谱马来布鲁线虫聚糖的IgG应答。我们鉴定出了广泛交叉反应以及特异性更强的聚糖靶点，拓展了当前对丝虫线虫糖基化与宿主抗聚糖抗体应答的有限认知。我们认为，本研究的初步发现可进一步被用于开发疾病特异性诊断方法，作为丝虫病防控整合策略的一部分。