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Transgenic Anopheles mosquitoes expressing human PAI-1 impair malaria transmission

Author

Listed:
  • Tales V. Pascini

    (National Institutes of Health)

  • Yeong Je Jeong

    (National Institutes of Health)

  • Wei Huang

    (Johns Hopkins Bloomberg School of Public Health)

  • Zarna R. Pala

    (National Institutes of Health)

  • Juliana M. Sá

    (National Institutes of Health)

  • Michael B. Wells

    (Johns Hopkins University School of Medicine
    Idaho College of Osteopathic Medicine)

  • Christopher Kizito

    (Johns Hopkins Bloomberg School of Public Health)

  • Brendan Sweeney

    (National Institutes of Health)

  • Thiago L. Alves e Silva

    (National Institutes of Health)

  • Deborah J. Andrew

    (Johns Hopkins University School of Medicine)

  • Marcelo Jacobs-­Lorena

    (Johns Hopkins Bloomberg School of Public Health)

  • Joel Vega-Rodríguez

    (National Institutes of Health)

Abstract

In mammals, the serine protease plasmin degrades extracellular proteins during blood clot removal, tissue remodeling, and cell migration. The zymogen plasminogen is activated into plasmin by two serine proteases: tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), a process regulated by plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor that specifically inhibits tPA and uPA. Plasmodium gametes and sporozoites use tPA and uPA to activate plasminogen and parasite-bound plasmin degrades extracellular matrices, facilitating parasite motility in the mosquito and the mammalian host. Furthermore, inhibition of plasminogen activation by PAI-1 strongly blocks infection in both hosts. To block parasite utilization of plasmin, we engineered Anopheles stephensi transgenic mosquitoes constitutively secreting human PAI-1 (huPAI-1) in the midgut lumen, in the saliva, or both. Mosquitoes expressing huPAI-1 strongly reduced rodent and human Plasmodium parasite transmission to mosquitoes, showing that co-opting plasmin for mosquito infection is a conserved mechanism among Plasmodium species. huPAI-1 expression in saliva induced salivary gland deformation which affects sporozoite invasion and P. berghei transmission to mice, resulting in significant levels of protection from malaria. Targeting the interaction of malaria parasites with the fibrinolytic system using genetically engineered mosquitoes could be developed as an intervention to control malaria transmission.

Suggested Citation

  • Tales V. Pascini & Yeong Je Jeong & Wei Huang & Zarna R. Pala & Juliana M. Sá & Michael B. Wells & Christopher Kizito & Brendan Sweeney & Thiago L. Alves e Silva & Deborah J. Andrew & Marcelo Jacobs-­, 2022. "Transgenic Anopheles mosquitoes expressing human PAI-1 impair malaria transmission," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30606-y
    DOI: 10.1038/s41467-022-30606-y
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    References listed on IDEAS

    as
    1. Junitsu Ito & Anil Ghosh & Luciano A. Moreira & Ernst A. Wimmer & Marcelo Jacobs-Lorena, 2002. "Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite," Nature, Nature, vol. 417(6887), pages 452-455, May.
    2. Olena Riabinina & Darya Task & Elizabeth Marr & Chun-Chieh Lin & Robert Alford & David A. O'Brochta & Christopher J. Potter, 2016. "Organization of olfactory centres in the malaria mosquito Anopheles gambiae," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
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