Pf CDPK1 is critical for malaria parasite gametogenesis and mosquito infection
| العنوان: | Pf CDPK1 is critical for malaria parasite gametogenesis and mosquito infection |
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| المؤلفون: | Yan Luo, Louis H. Miller, Yuesheng Li, Joseph Brzostowski, Abhisheka Bansal, Karthigayan Gunalan, Alvaro Molina-Cruz, José M. C. Ribeiro, Poching Liu |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Multidisciplinary, biology, Transgene, gametocytes, 030106 microbiology, Mutant, mosquito, Plasmodium falciparum, Biological Sciences, biology.organism_classification, Microbiology, Plasmodium, 3. Good health, compensation, Complementation, 03 medical and health sciences, 030104 developmental biology, plasmodium, PfCDPK1, Gametocyte, Parasite hosting, Gametogenesis |
| الوصف: | Significance We have shown in this study that the malaria parasite can rapidly evolve to adapt for loss of an “essential” kinase, PfCDPK1. PfCDPK1 could not be disrupted in the wild-type parasite. However, we were able to disrupt CDPK1 in the transgenic parasites adapted for reduced kinase activity of mutant PfCDPK1. Strategic disruption of PfCDPK1 highlights the importance of understanding the compensatory mechanisms, especially for targets belonging to multigene families. Our study unequivocally demonstrates that PfCDPK1 is critical for mosquito infections and its disruption leads to defective gametogenesis. Our study also suggests involvement of CDPK1 in regulation of sexual stage-specific genes during the asexual proliferation. Targeting PfCDPK1 may be a good strategy for developing transmission-blocking drugs. Efforts to knock out Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) from asexual erythrocytic stage have not been successful, indicating an indispensable role of the enzyme in asexual growth. We recently reported generation of a transgenic parasite with mutant CDPK1 [Bansal A, et al. (2016) MBio 7:e02011-16]. The mutant CDPK1 (T145M) had reduced activity of transphosphorylation. We reasoned that CDPK1 could be disrupted in the mutant parasites. Consistent with this assumption, CDPK1 was successfully disrupted in the mutant parasites using CRISPR/Cas9. We and others could not disrupt PfCDPK1 in the WT parasites. The CDPK1 KO parasites show a slow growth rate compared with the WT and the CDPK1 T145M parasites. Additionally, the CDPK1 KO parasites show a defect in both male and female gametogenesis and could not establish an infection in mosquitoes. Complementation of the KO parasite with full-length PfCDPK1 partially rescued the asexual growth defect and mosquito infection. Comparative global transcriptomics of WT and the CDPK1 KO schizonts using RNA-seq show significantly high transcript expression of gametocyte-specific genes in the CDPK1 KO parasites. This study conclusively demonstrates that CDPK1 is a good target for developing transmission-blocking drugs. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e7d9c9dd0cd2b0b9df7aaffae4eebc12 https://doi.org/10.1073/pnas.1715443115 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e7d9c9dd0cd2b0b9df7aaffae4eebc12 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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