A comprehensive map detailing all the essential genes involved in blood infections caused by *Plasmodium knowlesi* (*P. knowlesi*), a malaria-causing parasite in humans, has been created by researchers from Harvard T.H. Chan School of Public Health and their collaborators. This map represents the most extensive classification of crucial genes found in any *Plasmodium* species and will aid in locating potential drug targets within the parasite as well as understanding drug resistance mechanisms, which can assist in the development of novel malaria treatments.
Researchers from Harvard T.H. Chan School of Public Health, along with others, have generated a comprehensive map of all the genes vital for blood infections in Plasmodium knowlesi (P. knowlesi), a parasite responsible for malaria in humans. This map provides the most detailed classification of essential genes in any Plasmodium species and can be utilized to discover druggable targets in the parasite and understand drug resistance mechanisms, informing the creation of new malaria therapies.
“We aspire that our discoveries significantly advance malaria research and control efforts,” stated co-corresponding author Manoj Duraisingh, the John LaPorte Given Professor of Immunology and Infectious Diseases. “Rising drug resistance to the limited number of available antimalarial drugs poses a significant challenge. This mapping will serve as an invaluable tool for researchers striving to address one of the leading causes of infectious disease-related deaths worldwide.”
The findings are set to be published on February 6, 2025, in Science.
Approximately 249 million cases of malaria, caused by various Plasmodium species, occur annually, leading to around 608,000 fatalities. P. knowlesi is one of the species contributing to human malaria. It is a zoonotic parasite that poses serious health risks and is increasingly concerning public health in Southeast Asia.
The team employed a sophisticated genetic technique called transposon mutagenesis in P. knowlesi to disrupt all genes not necessary for growth within human red blood cells, thereby mapping the essential genes required for growth. This technique enabled them to identify the key molecular conditions for the parasite’s proliferation. The researchers successfully identified specific genes associated with resistance to existing antimalarials.
“Identifying all essential genes in P. knowlesi enhances our understanding of the molecular tactics employed by the parasite for growth, adaptation to environmental shifts, and response to treatments like antimalarials,” remarked co-first author Sheena Dass, a postdoctoral fellow in the Department of Immunology and Infectious Diseases. “This molecular framework will be instrumental for malaria researchers in planning and conducting biological investigations as well as developing strategies to monitor and curb the rise of drug resistance.”
The research also offers valuable insights into another malaria-causing Plasmodium species, P. vivax, due to their evolutionary connections. P. vivax is challenging to study as it cannot be cultured or genetically manipulated, complicating eradication efforts.
Brendan Elsworth and Sida Ye served as co-first authors, while Kourosh Zarringhalam from the University of Massachusetts, Boston, was a co-corresponding author.
Additional co-authors from Harvard Chan include Jacob Tennessen, Basil Thommen, Aditya Paul, Usheer Kanjee, and Christof Gruring.
This study was funded by the National Institutes of Health (grants 5R01AI168163, 5R01 AI167570, ORIP/OD P51OD011132, and U42 PDP11023); Swiss National Science Foundation Postdoc Mobility (fellowships PBSKP3_140144 and P300P3_151146); and the Food and Drug Administration Intramural Research Program.
