Biochemical characterization and evaluation of a Brugia malayi small heat shock protein as a vaccine against lymphatic filariasis.
Biochemical characterization and evaluation of a Brugia malayi small heat shock protein as a vaccine against lymphatic filariasis.
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DOI：
10.1371/journal.pone.0034077
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kalyanasundaram R
中科院分区：
文献类型：
--
作者：
Dakshinamoorthy G;Samykutty AK;Munirathinam G;Shinde GB;Nutman T;Reddy MV;Kalyanasundaram R
由于寄生虫开发的有效免疫逃避策略，丝虫线虫享有任何人类病原体中最长的寿命之一。在寄生虫表现出的各种免疫逃避策略中，白细胞介素10（IL-10）的产生和IL-10介导的免疫抑制对宿主免疫系统具有显著的负面影响。最近，我们鉴定了由马来丝虫表达的小热休克蛋白（BmHsp12.6），其可以结合可溶性人IL-10受体α（IL-10R）并激活细胞系中IL-10介导的效应。在这项研究中，我们表明，BmHsp12.6的IL-10 R结合区定位于其N-末端区域。该区域与人IL-10的受体结合区具有显著的序列相似性。体外研究证实BmHsp12.6的N端区域（N-BmHsp12.6）具有IL-10样活性，而含有α晶体结构域和C端的区域（BmHsp12.6 α c）不具有IL-10样活性。而BmHsp 12.6 α c含有B细胞、T细胞和CTL表位。sHSP家族成员是优秀的疫苗候选者。对免疫性地方病（EN）人群血清进行检测，结果显示抗BmHsp12.6 α c的IgG1和IgG3抗体参与ADCC介导的保护作用。随后使用异源初免加强方法在小鼠模型中进行的BmHsp 12.6 α c疫苗接种试验显示，可实现83%的抗B保护。马来语L3挑战。结果表明，BmHsp12.6的N-BmHsp12.6亚基具有免疫调节功能，而BmHsp12.6的α c亚基具有重要的疫苗潜力。
Filarial nematodes enjoy one of the longest life spans of any human pathogen due to effective immune evasion strategies developed by the parasite. Among the various immune evasion strategies exhibited by the parasite, Interleukin 10 (IL-10) productions and IL-10 mediated immune suppression has significant negative impact on the host immune system. Recently, we identified a small heat shock protein expressed by Brugia malayi (BmHsp12.6) that can bind to soluble human IL-10 receptor alpha (IL-10R) and activate IL-10 mediated effects in cell lines. In this study we show that the IL-10R binding region of BmHsp12.6 is localized to its N-terminal region. This region has significant sequence similarity to the receptor binding region of human IL-10. In vitro studies confirm that the N-terminal region of BmHsp12.6 (N-BmHsp12.6) has IL-10 like activity and the region containing the alpha crystalline domain and C-terminus of BmHsp12.6 (BmHsp12.6αc) has no IL-10 like activity. However, BmHsp12.6αc contains B cell, T cell and CTL epitopes. Members of the sHSP families are excellent vaccine candidates. Evaluation of sera samples from putatively immune endemic normal (EN) subjects showed IgG1 and IgG3 antibodies against BmHsp12.6αc and these antibodies were involved in the ADCC mediated protection. Subsequent vaccination trials with BmHsp12.6αc in a mouse model using a heterologous prime boost approach showed that 83% protection can be achieved against B. malayi L3 challenge. Results presented in this study thus show that the N-BmHsp12.6 subunit of BmHsp12.6 has immunoregulatory function, whereas, the BmHsp12.6αc subunit of BmHsp12.6 has significant vaccine potential.