Summary of project PR002442
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002442. The data can be accessed directly via it's Project DOI: 10.21228/M80544 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002442 |
| Project DOI: | doi: 10.21228/M80544 |
| Project Title: | Neither Plasmodium falciparum Plasmepsin Copy Number Nor Piperaquine Treatment Impact Hemoglobin Digestion |
| Project Summary: | Malaria is still a major health issue in many parts of the world, particularly in tropical and subtropical regions of Africa, Asia, and Latin America. Despite significant efforts to control and eliminate the disease, malaria remains a leading cause of illness and death, mainly due to the occurrence of drug-resistant parasites to the frontline antimalarials such as dihydroartemisinin-piperaquine (DHA-PPQ). Partial artemisinin resistance has been linked to kelch13 mutations, while decreased PPQ sensitivity has been associated with higher plasmepsin II and III gene copies and mutations in the chloroquine resistance transporter. In this study, we demonstrate the effective use of CRISPR/Cas9 technology to generate single knockouts (KO) of plasmepsin II and plasmepsin III, as well as a double KOs of both genes, in two isogenic lines of Cambodian parasites with varying numbers of plasmepsin gene copies. The deletion of plasmepsin II and/or III increased the parasites' sensitivity to PPQ, evaluated by the area under the curve. We explored several hypotheses to understand how an increased plasmepsin gene copy number might influence parasite survival under high PPQ pressure. Our findings indicate that protease inhibitors have a minimal impact on parasite susceptibility to PPQ. Additionally, parasites with higher plasmepsin gene copy numbers did not exhibit significantly increased hemoglobin digestion, nor did they produce different amounts of free heme following PPQ treatment compared to wildtype parasites. Interestingly, hemoglobin digestion was slowed in parasites with plasmepsin II deletions. By treating parasites with digestive vacuole (DV) function modulators, we found that changes in DV pH potentially affect their response to PPQ. Our research highlights the crucial role of increased plasmepsin II and III gene copy numbers in modulating response to PPQ and begins to uncover the molecular and physiological mechanisms underlying PPQ resistance in Cambodian parasites. |
| Institute: | Pennsylvania State University |
| Department: | Biochemistry and Molecular Biology |
| Laboratory: | Manuel Llinás |
| Last Name: | Rangel |
| First Name: | Gabriel |
| Address: | 491 Pollock Road, University Park, PA, 16802, USA |
| Email: | gwr5170@psu.edu |
| Phone: | 8148673527 |
Summary of all studies in project PR002442
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST003902 | Plasmodium falciparum plasmepsin copy number and piperaquine treatment have no effect of hemoglobin digestion | Plasmodium falciparum | Pennsylvania State University | MS | 2025-05-28 | 1 | 84 | Uploaded data (2.3G)* |
| ST003904 | Plasmodium falciparum plasmepsin copy number and piperaquine treatment have no effect of hemoglobin digestion - Negative Mode | Plasmodium falciparum | Pennsylvania State University | MS | 2025-05-28 | 1 | 84 | Uploaded data (4.3G)* |
| ST003906 | Neither Plasmodium falciparum Plasmepsin Copy Number Nor Piperaquine Treatment Impact Hemoglobin Digestion | Plasmodium falciparum | Pennsylvania State University | MS | 2025-05-28 | 1 | 62 | Uploaded data (2.6G)* |
