TY - JOUR
T1 - Transgenic Anopheles mosquitoes expressing human PAI-1 impair malaria transmission
AU - Pascini, Tales V.
AU - Jeong, Yeong Je
AU - Huang, Wei
AU - Pala, Zarna R.
AU - Sá, Juliana M.
AU - Wells, Michael B.
AU - Kizito, Christopher
AU - Sweeney, Brendan
AU - Alves e Silva, Thiago L.
AU - Andrew, Deborah J.
AU - Jacobs-Lorena, Marcelo
AU - Vega-Rodríguez, Joel
N1 - Funding Information:
We thank André Laughinghouse, Kevin Lee, and Yonas Gebremicale for insectary support, the Insectary and Parasite Core Facilities of the Johns Hopkins Malaria Research Institute; Dr. Milton J. Herrera, John Graves, and Surika Maharaj, at the Division of Veterinary Resources, NIH, for technical assistance with non-human primates; Dr. Christopher Potter for providing plasmids for the generation of transgenic mosquitoes, Dr. Carolina Barilla-Mury (anti-IMPer), Dr. Eric Calvo (anti-salivary gland extract antibody), and Dr. Photini Sinnis (anti-CSP and anti-TRAP) for providing antibodies, and Dr. Thomas Wellems for insightful discussions. This work was supported by NIH Distinguished Scholars Program and the Intramural Research Program of the Division of Intramural Research AI001250-01, NIAID, National Institutes of Health, the National Institutes of Health (R01AI031478 to M.J.L.), the Johns Hopkins Malaria Research Institute Insectary and Parasite Core Facilities, the Bloomberg Philanthropies. Supply of human blood was supported by the National Institutes of Health grant RR00052.
Funding Information:
We thank André Laughinghouse, Kevin Lee, and Yonas Gebremicale for insectary support, the Insectary and Parasite Core Facilities of the Johns Hopkins Malaria Research Institute; Dr. Milton J. Herrera, John Graves, and Surika Maharaj, at the Division of Veterinary Resources, NIH, for technical assistance with non-human primates; Dr. Christopher Potter for providing plasmids for the generation of transgenic mosquitoes, Dr. Carolina Barilla-Mury (anti-IMPer), Dr. Eric Calvo (anti-salivary gland extract antibody), and Dr. Photini Sinnis (anti-CSP and anti-TRAP) for providing antibodies, and Dr. Thomas Wellems for insightful discussions. This work was supported by NIH Distinguished Scholars Program and the Intramural Research Program of the Division of Intramural Research AI001250-01, NIAID, National Institutes of Health, the National Institutes of Health (R01AI031478 to M.J.L.), the Johns Hopkins Malaria Research Institute Insectary and Parasite Core Facilities, the Bloomberg Philanthropies. Supply of human blood was supported by the National Institutes of Health grant RR00052.
Publisher Copyright:
© 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85130758003&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-30606-y
DO - 10.1038/s41467-022-30606-y
M3 - Article
C2 - 35618711
AN - SCOPUS:85130758003
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2949
ER -