Ricciardi Alessandra, Hassan Sergio A, Kamenyeva Olena, Bennuru Sasisekhar, Andersen John, Nutman Thomas B
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
PNAS Nexus. 2022 Sep 7;1(4):pgac184. doi: 10.1093/pnasnexus/pgac184. eCollection 2022 Sep.
Interleukin (IL)-10 is the primary cytokine driving the modulation of the host response in filarial infections. We performed binding assays with antigen extracts and human IL-10R1. Bm5539 was the top-binding hit. We identified a short sequence, termed truncated Bm5339, that has structural similarities to the human IL-10 functional dimer. Sequence comparisons revealed that other filarial parasites possess Bm5539 orthologues. Using recombinant Bm5539 in a modified Luciferase Immunoprecipitation System assay, we confirmed that both the truncated and full-length forms of the protein can bind to human IL-10R1. Truncated Bm5539 could inhibit human IL-10-driven phosphorylation of STAT3, thereby demonstrating that Bm5539 acts as an IL-10 antagonist, most likely through competitive binding to the receptor. We provide a structural basis for these observations using computational modeling and simulations. This parasite-encoded cytokine receptor antagonist provides an additional lens through which parasite-induced modulation of the host immune response can be examined.
白细胞介素（IL）-10是驱动丝虫感染中宿主反应调节的主要细胞因子。我们用抗原提取物和人IL-10R1进行了结合试验。Bm5539是结合力最强的。我们鉴定出一个短序列，称为截短型Bm5339，它与人类IL-10功能二聚体具有结构相似性。序列比较显示，其他丝虫寄生虫也有Bm5539的直系同源物。在改良的荧光素酶免疫沉淀系统试验中使用重组Bm5539，我们证实该蛋白的截短型和全长型都能与人IL-10R1结合。截短型Bm5539可抑制人IL-10驱动的STAT3磷酸化，从而证明Bm5539作为一种IL-10拮抗剂，很可能是通过与受体竞争性结合发挥作用。我们使用计算建模和模拟为这些观察结果提供了结构基础。这种寄生虫编码的细胞因子受体拮抗剂为研究寄生虫诱导的宿主免疫反应调节提供了一个新视角。
