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Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):774-779. doi: 10.1073/pnas.1715443115. Epub 2018 Jan 8.

PfCDPK1 is critical for malaria parasite gametogenesis and mosquito infection.

Author information

1
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20851; bansal.abhisheka@gmail.com lmiller@niaid.nih.gov.
2
School of Life Sciences, Jawaharlal Nehru University, New Delhi, India 110067.
3
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20851.
4
LIG Imaging Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20851.
5
DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.

Abstract

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.

KEYWORDS:

PfCDPK1; compensation; gametocytes; mosquito; plasmodium

PMID:
29311293
PMCID:
PMC5789930
DOI:
10.1073/pnas.1715443115
[Indexed for MEDLINE]
Free PMC Article

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