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Plasmodium falciparum has evolved multiple mechanisms to hijack human immunoglobulin M

Author

Listed:
  • Chenggong Ji

    (Peking University
    Changping Laboratory)

  • Hao Shen

    (Peking University)

  • Chen Su

    (Peking University)

  • Yaxin Li

    (Peking University)

  • Shihua Chen

    (Peking University)

  • Thomas H. Sharp

    (Leiden University Medical Center)

  • Junyu Xiao

    (Peking University
    Changping Laboratory
    Peking University)

Abstract

Plasmodium falciparum causes the most severe malaria in humans. Immunoglobulin M (IgM) serves as the first line of humoral defense against infection and potently activates the complement pathway to facilitate P. falciparum clearance. A number of P. falciparum proteins bind IgM, leading to immune evasion and severe disease. However, the underlying molecular mechanisms remain unknown. Here, using high-resolution cryo-electron microscopy, we delineate how P. falciparum proteins VAR2CSA, TM284VAR1, DBLMSP, and DBLMSP2 target IgM. Each protein binds IgM in a different manner, and together they present a variety of Duffy-binding-like domain-IgM interaction modes. We further show that these proteins interfere directly with IgM-mediated complement activation in vitro, with VAR2CSA exhibiting the most potent inhibitory effect. These results underscore the importance of IgM for human adaptation of P. falciparum and provide critical insights into its immune evasion mechanism.

Suggested Citation

  • Chenggong Ji & Hao Shen & Chen Su & Yaxin Li & Shihua Chen & Thomas H. Sharp & Junyu Xiao, 2023. "Plasmodium falciparum has evolved multiple mechanisms to hijack human immunoglobulin M," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38320-z
    DOI: 10.1038/s41467-023-38320-z
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    References listed on IDEAS

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    1. Saurabh Kumar Singh & Rachna Hora & Hassan Belrhali & Chetan E. Chitnis & Amit Sharma, 2006. "Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain," Nature, Nature, vol. 439(7077), pages 741-744, February.
    2. Kaituo Wang & Robert Dagil & Thomas Lavstsen & Sandeep K. Misra & Charlotte B. Spliid & Yong Wang & Tobias Gustavsson & Daniel R. Sandoval & Elena Ethel Vidal-Calvo & Swati Choudhary & Mette Ø Agerbae, 2021. "Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
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    Cited by:

    1. Reetesh Raj Akhouri & Suchi Goel & Ulf Skoglund, 2023. "Cryo-electron microscopy of IgM-VAR2CSA complex reveals IgM inhibits binding of Plasmodium falciparum to Chondroitin Sulfate A," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Yuxin Wang & Chen Su & Chenggong Ji & Junyu Xiao, 2024. "CD5L associates with IgM via the J chain," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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