Turning Our Enemies Into Allies: A New Approach in Parasitology
Malaria is a type of parasitic infectious disease transmitted to humans via the saliva of infected mosquitoes. Annually, over 200 million people contract the disease, causing approximately 600,000 deaths worldwide. Among the different types of the disease, falciparum malaria is the most prevalent and leads to a high mortality rate.
In 2021, Associate Professor Naoyuki Fukuda, in collaboration with Professor Toshihiro Mita and Assistant Professor Betty Balikagala of the Department of Tropical Medicine and Parasitology at Juntendo University School of Medicine, joined with research teams from Gulu University (Uganda), Osaka University, and Nagasaki University, and noted the emergence of artemisinin-resistant malaria in Africa. Artemisinin serves as the primary treatment for falciparum malaria, and malarial parasites resistant to it is a significant global health concern. Furthermore, Dr. Fukuda, having previously focused on studying drug resistance in malarial parasites, has now launched an innovative research project aimed at turning parasitic enemies into allies, exploring how malaria parasites could be utilized for treating non-infectious diseases.
Professor Toshihiro Mita’s research group has been monitoring drug-resistant malaria in Uganda and, in 2018, reported evidence of artemisinin resistance at the parasite level. Around this time, I had become fully engaged in focusing on clinical drug resistance surveys and genomic analyses. In 2021, we were able to confirm the emergence of resistant malaria parasites following the WHO criteria for artemisinin resistance and identified two mutations in the kelch13 gene as the underlying cause for this resistance.
While artemisinin-resistant malaria parasites have been spreading in Southeast Asia since the late 2000s, they were previously believed to be absent in Africa. Our 2021 report was the first to challenge this assumption, though similar findings were being reported simultaneously by other groups from Rwanda. This discovery headlined the global health news, driving large-scale research efforts across Africa and influencing policies on infectious disease at the WHO and in some countries.
My primary contribution to this study was genetic analysis, in addition to, on-site surveys conducted in Africa. To assess the standalone efficacy of artemisinin, which is typically used in combination with other antimalarial drugs, we administered artemisinin monotherapy to hospitalized malaria patients and closely analyzed its therapeutic effects through their blood sample examinations. Among the 240 patients enrolled in the study, 14 of them (5.8%) met the WHO criteria for artemisinin resistance, and 13 patients carried either an A675V or a C469Y mutation at the kelch13 gene—mutations that were known to confer artemisinin resistance. The study further revealed that by 2019, parasites carrying the A675V and C469Y mutations had increased to a cumulative 16%, compared to their complete absence in 2015. Additionally, a comparative genomic analysis with malaria parasites from the Greater Mekong Subregion of Southeast Asia demonstrated that artemisinin-resistant parasites in Africa exhibited distinct genetic characteristics. While Professor Mita and his team deserve significant recognition for this groundbreaking discovery, their meticulous approach—even in aspects often overlooked—has been particularly influential in shaping my research.
As a member of Professor Mita’s team, I am currently part of our international collaborative field research aimed at developing strategies to control drug-resistant malaria. Parallelly, I am also investigating the factors that promote the acquisition of artemisinin resistance in Plasmodium falciparum and its correlation with the ability of infected red blood cells to adhere to vascular endothelium. Unlike other malaria parasites that circulate freely in the bloodstream, P. falciparum-infected red blood cells bind to the vascular endothelium, amplifying the disease severity. Additionally, many individuals in Africa have developed partial immunity to malaria, leading to variations in drug efficacy among patients. While drug resistance is often studied from the parasite’s perspective, I believe host factors also play a significant role. To fully understand malaria parasite drug resistance, we thought of integrating the two defining characteristics of P. falciparum—its high potential for developing drug resistance and its propensity to cause severe disease—into a unified framework. This novel approach has been recognized and supported by the Grant in Aid for Scientific Research (B).
The emergence of drug resistance, including artemisinin resistance, has resulted in a continuous ‘cat and mouse’ dynamic where each new treatment is eventually met with resistance. This research not only aims to monitor emerging resistance but also seeks to uncover the mechanisms by which resistance is acquired, ultimately striving to prevent its occurrence altogether. Our findings indicate that higher levels of Plasmodium falciparum-infected red blood cells adhering to the vascular endothelium are associated with reduced susceptibility to artemisinin. Building on this, we plan to further investigate how the parasite’s environment within the human body influences its drug susceptibility.
Since 2023, we have been conducting a research project titled “Development of New Treatments Using the Multifunctionalization of Red Blood Cells by Modified Malaria Parasites,” supported by the Japan Science and Technology agency (JST). This project stems from a bold shift in perspective—transforming malaria parasites, targets for eradication, into potential allies for medical applications! I had envisioned this research for years. In fact, before joining Juntendo University, I had discussed this concept with Professor Mita as a challenge I aspired to pursue. After extensive preparation and effort, I am finally able to bring it to fruition now.
Malaria parasites infect red blood cells, but when we look at it from a different perspective, during this process, a nucleus-free cell (the red blood cell) acquires a nucleus externally. Given that red blood cells are structurally simple and widely used in clinical practice through transfusion, leveraging malaria parasites to impart new functions to red blood cells could open novel therapeutic possibilities. While viruses and bacteria have been explored for medical applications, utilizing complex organisms like parasites presents significant challenges. To address this, we are employing genome editing and other advanced techniques to develop an innovative “dream parasite”—one that selectively accumulates at disease sites, targets and attacks them, and then disappears once its therapeutic function is complete.
This research is still in its early stages and presents significant challenges. However, in line with the objectives of the JST, we are committed to pursuing this bold idea with a spirit of scientific exploration.
I have dedicated my research to the field of parasitology, a crucial area of medical research. While the demand for parasitology remains high in many countries overseas, in Japan, the field is unfortunately often overlooked, with fewer universities offering courses in this discipline. However, this field is a treasure trove of undiscovered breakthroughs. While my current focus is on basic research in the laboratory, I believe my experiences in clinical settings and overseas field surveys have provided me with a dynamic perspective, allowing me to approach research from both micro and macro levels. Leveraging my past research experiences, I hope to explore the research themes supported by the JST and highlight new possibilities within parasitology, contributing to advanced medical care. As a researcher fascinated by the nature of this field, I aim to improve awareness regarding the value of parasitology for future generations.
Research is inherently competitive, but instead of focusing on the competition, I would like to produce groundbreaking results that offer a unique and original perspective. Juntendo University provides a robust support system for researchers adopting new technologies, and the JST helps me forge new connections with leading researchers in the field, keeping me inspired and motivated. I am committed to leveraging this environment to propel my research forward and take on the challenge of conducting work that will one day leave a lasting impact on the world.
Department of Tropical Medicine and Parasitology, Juntendo University
Faculty of Medicine
Associate Professor
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