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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Evasion of immunity to Plasmodium falciparum malaria by IgM masking of protective IgG epitopes in infected erythrocyte surface-exposed PfEMPI
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Evasion of immunity to Plasmodium falciparum malaria by IgM masking of protective IgG epitopes in infected erythrocyte surface-exposed PfEMPI

机译：通过IgM掩盖感染的红细胞表面暴露的PfEMPI中的保护性IgG表位，避免对恶性疟原虫疟疾产生免疫力

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摘要

Plasmodium falciparum malaria is a major cause of mortality and severe morbidity. Its virulence is related to the parasite's ability to evade host immunity through clonal antigenic variation and tissue-specific adhesion of infected erythrocytes (lEs). The P. falciparum erythrocyte membrane protein 1 (PfEMPI) family is central to both. Here, we present evidence of a P. falciparum evasion mechanism not previously documented: the masking of PfEMPI-specific IgG epitopes by nonspecific IgM. Nonspecific IgM binding to erythrocytes infected by parasites expressing the PfEMPI protein VAR2CSA (involved in placental malaria pathogenesis and protective immunity) blocked subsequent specific binding of human monoclonal IgG to the Duffy binding-like (DBL) domains DBL3X and DBL5e of this PfEMPI variant. Strikingly, a VAR2CSA-specific monoclonal antibody that binds outside these domains and can inhibit IE adhesion to the specific VAR2CSA receptor chondroitin sulfate A was unaffected. Nonspecific IgM binding protected the parasites from FcyR-dependent phagocytosis of VAR2CSA~+ lEs, but it did not affect IE adhesion to chondroitin sulfate A or lead to C1q deposition on lEs. Taken together, our results indicate that the VAR2CSA affinity for nonspecific IgM has evolved to allow placenta-sequestering P. falciparum to evade acquired protective immunity without compromising VAR2CSA function or increasing IE susceptibility to complement-mediated lysis. Furthermore, functionally important PfEMPI epitopes not prone to IgM masking are likely to be particularly important targets of acquired protective immunity to P. falciparum malaria.
机译：恶性疟原虫疟疾是死亡和严重发病的主要原因。它的毒力与寄生虫通过克隆抗原变异和感染的红细胞（lEs）的组织特异性粘附逃避宿主免疫的能力有关。恶性疟原虫红细胞膜蛋白1（PfEMPI）家族是这两者的核心。在这里，我们提供了以前没有文献记载的恶性疟原虫逃避机制的证据：非特异性IgM对PfEMPI特异性IgG表位的掩盖。与表达PfEMPI蛋白VAR2CSA的寄生虫感染的红细胞的非特异性IgM结合（涉及胎盘疟疾发病机制和保护性免疫）阻止了人类单克隆IgG随后与该PfEMPI变体的Duffy结合样（DBL）域DBL3X和DBL5e特异性结合。令人惊讶的是，VAR2CSA特异性单克隆抗体不受影响，这些单克隆抗体可在这些域外部结合并抑制IE对特定VAR2CSA受体硫酸软骨素A的粘附。 IgM的非特异性结合可以保护寄生虫免受VAR2CSA〜+ IE的FcyR依赖性吞噬作用，但它不会影响IE对硫酸软骨素A的粘附或导致C1q在IE上的沉积。两者合计，我们的结果表明，VAR2CSA对非特异性IgM的亲和力已经进化为允许胎盘隔离恶性疟原虫逃避获得性保护性免疫，而不会损害VAR2CSA功能或增加IE对补体介导的裂解的敏感性。此外，在功能上重要的不易被IgM掩盖的PfEMPI表位可能是获得针对恶性疟原虫疟疾的保护性免疫的特别重要的目标。

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  • 作者

    Lea Barfod; Michael B. Dalgaard; Suzan T. Pleman; Michael F. Ofori; Richard J. Pleass; Lars Hviid;

  • 作者单位

    Centre for Medical Parasitology, Department of International Health, Immunology, and Microbiology, University of Copenhagen, 2200 Copenhagen,Denmark,Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark;

    Centre for Medical Parasitology, Department of International Health, Immunology, and Microbiology, University of Copenhagen, 2200 Copenhagen,Denmark,Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark;

    Centre for Medical Parasitology, Department of International Health, Immunology, and Microbiology, University of Copenhagen, 2200 Copenhagen,Denmark,Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark;

    Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana;

    Molecular and Biochemical Parasitology Group, Liverpool School of Tropical Medicine, Liverpool L35QA, United Kingdom;

    Centre for Medical Parasitology, Department of International Health, Immunology, and Microbiology, University of Copenhagen, 2200 Copenhagen,Denmark,Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    evolutionary selection; immunoevasion; sequestration; pregnancy;

    机译：进化选择;免疫逃避;隔离;妊娠;

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