Transgenic Anopheles mosquitoes expressing human PAI-1 impair malaria transmission

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-­Lorena and Joel Vega-Rodríguez ()
Additional contact information
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30606-y

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