In a landmark study published in Science on February 6, 2025, researchers from Harvard T.H. Chan School of Public Health and their collaborators have unveiled a comprehensive map of all the genes essential for blood infections in Plasmodium knowlesi (P. knowlesi), a malaria-causing parasite. This groundbreaking work provides the most complete classification of essential genes in any Plasmodium species to date, offering unprecedented insights into drug resistance mechanisms and identifying potential targets for new antimalarial therapies.
The study, titled “The Essential Genome of Plasmodium knowlesi Reveals Determinants of Antimalarial Susceptibility,” represents a significant leap forward in the fight against malaria, a disease that continues to claim hundreds of thousands of lives annually. With emerging resistance to existing antimalarial drugs posing a growing threat, this research provides a critical resource for understanding the molecular strategies employed by the parasite and developing innovative solutions to combat its spread.
A Global Health Crisis
Malaria remains one of the most devastating infectious diseases worldwide, with an estimated 249 million human cases and approximately 608,000 deaths reported annually. The disease is caused by parasites of the Plasmodium genus, with P. knowlesi being one of several species responsible for human infections. While P. knowlesi is zoonotic—originating in animals—it has become an emerging public health concern in Southeast Asia due to its potential lethality and increasing prevalence.
Despite significant progress in malaria control over the past two decades, the rise of drug-resistant strains has undermined efforts to eliminate the disease. The current arsenal of antimalarial drugs is limited, and resistance to key treatments, such as artemisinin-based combination therapies, is spreading. This underscores the urgent need for new therapeutic strategies and a deeper understanding of the parasite’s biology.
Unlocking the Parasite’s Genetic Blueprint
To address this challenge, the research team employed a powerful genetic technique known as transposon mutagenesis. This approach allowed them to systematically disrupt genes in P. knowlesi that are not essential for its growth in human red blood cells. By doing so, they identified the complete set of genes critical for the parasite’s survival, creating a detailed map of its essential genome.
“This map is a game-changer for malaria research,” said co-corresponding author Manoj Duraisingh, the John LaPorte Given Professor of Immunology and Infectious Diseases at Harvard T.H. Chan School of Public Health. “It provides a comprehensive view of the molecular requirements for P. knowlesi to grow and thrive, offering valuable insights into how the parasite responds to environmental changes and therapeutic interventions.”
The study not only revealed the essential genes required for the parasite’s growth but also pinpointed specific genes associated with resistance to current antimalarial drugs. This information is critical for understanding how resistance develops and for designing new drugs that can overcome these mechanisms.
Implications for Malaria Research and Control
The findings have far-reaching implications for both basic research and applied efforts to control malaria. By identifying the essential genes in P. knowlesi, the study provides a molecular blueprint that can guide the development of targeted therapies. Additionally, the insights gained from this research can be applied to other malaria-causing parasites, including Plasmodium vivax (P. vivax), which is closely related to P. knowlesi but has been notoriously difficult to study due to its inability to be cultured in the lab.
“Understanding the essential genes in P. knowlesi allows us to infer critical biological processes in P. vivax, which is a major obstacle to malaria elimination efforts,” explained co-first author Sheena Dass, a postdoctoral fellow in the Department of Immunology and Infectious Diseases. “This knowledge will help researchers design more effective strategies to monitor and combat drug resistance.”
The study also highlights the importance of interdisciplinary collaboration in tackling complex global health challenges. The research team included experts in genetics, molecular biology, and computational analysis, working together to generate and interpret the vast amounts of data produced by the study.
A Collaborative Effort
The study was led by a team of researchers from Harvard T.H. Chan School of Public Health, including co-first authors Brendan Elsworth and Sida Ye, and co-corresponding author Kourosh Zarringhalam from the University of Massachusetts, Boston. Other contributors from Harvard Chan included Jacob Tennessen, Basil Thommen, Aditya Paul, Usheer Kanjee, and Christof Grüring.
The research was supported by grants from the National Institutes of Health (NIH), including 5R01AI168163, 5R01 AI167570, ORIP/OD P51OD011132, and U42 PDP11023. Additional funding was provided by the Swiss National Science Foundation Postdoc Mobility Fellowships (PBSKP3_140144 and P300P3_151146) and the Food and Drug Administration Intramural Research Program.
Looking Ahead
The publication of this study marks a significant milestone in malaria research, but the work is far from over. The researchers emphasize that the map of P. knowlesi’s essential genome is a starting point for further investigations into the parasite’s biology and its interactions with human hosts. Future studies will focus on validating the identified drug targets and exploring how the findings can be translated into practical solutions for malaria control.
“We hope that this research will inspire new approaches to drug development and resistance management,” said Duraisingh. “By leveraging the insights from this study, we can move closer to our ultimate goal of eliminating malaria as a public health threat.”
About Harvard T.H. Chan School of Public Health
Harvard T.H. Chan School of Public Health is a global leader in public health research, education, and practice. Founded in 1913 as the first professional training program in public health in the United States, the School has a long history of addressing the world’s most pressing health challenges. Its mission is to improve health and advance equity through innovative research, education, and collaboration.
The School’s faculty, students, and alumni are at the forefront of efforts to combat infectious diseases, promote environmental justice, strengthen health systems, and improve health outcomes for populations around the world. Through its degree programs, postdoctoral training, fellowships, and continuing education courses, Harvard Chan School educates thousands of public health leaders each year.
For More Information
To learn more about this study and other research initiatives at Harvard T.H. Chan School of Public Health, visit the School’s website or contact Maya Brownstein, Media Relations Manager, at [email protected].
Citation
Elsworth, B., Ye, S., Dass, S., Tennessen, J. A., Sultana, Q., Thommen, B. T., Paul, A. S., Kanjee, U., Grüring, C., Ferreira, M. U., Gubbels, M.-J., Zarringhalam, K., & Duraisingh, M. T. (2025). The essential genome of Plasmodium knowlesi reveals determinants of antimalarial susceptibility. Science. doi:10.1126/science.adq6241
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About the Author
Maya Brownstein is the Media Relations Manager in the Office of Communications at Harvard T.H. Chan School of Public Health. With a background in science communication, she works to share the School’s research and impact with global audiences.
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