Genome-wide protein study of Plasmodium falciparum malaria

Malaria is an infectious disease caused by a small eukaryotic organism that is transmitted through the bite of a mosquito (a special type of mosquito called the hamadry mosquito). Its main symptoms are fever and anemia, etc. About 250 million people are infected annually, and 600,000 die. Malaria is a “mosquito parasite” that reproduces sexually in mosquitoes, and humans are like “ranch animals,” so to speak. The figure shows the life cycle of malaria. Sporozoites that enter the body with the mosquito’s saliva infect the liver and are released into the bloodstream as merozoites that infect red blood cells in about 12 days. During this time, there are no subjective symptoms at all. The merozoites infect the red blood cells and repeatedly multiply 20-fold in 48 hours. The red blood cells are then destroyed, resulting in fever and anemia. The reproductive mother is sucked by the mosquito and reproduces sexually in the mosquito’s intestines.

Malaria is treated with chemotherapeutic agents, and if appropriate treatment is received early, death is not common (although it is difficult). However, with the emergence of drug-resistant Plasmodium falciparum, new countermeasures have become necessary. Therefore, there is a need to develop new malaria vaccines and diagnostic methods.

Life Cycle of Malaria

Research Overview

Malaria is not endemic in Japan and you have probably never been infected with it. Will malaria become more prevalent in Japan if global warming continues? Malaria is often thought of as a tropical disease, but it is known that in prewar Japan, it was also contracted by Tonden soldiers in Hokkaido. The reason malaria is not prevalent in modern Japan is that the habitat of the Asian Hamadara mosquito is limited to mountain streams at the foot of mountains. For the same reason, there is almost no malaria epidemic in Thailand in urban areas such as Bangkok. Therefore, it is unlikely that malaria will become endemic in Japan due to global warming.

Then, why is malaria research being conducted in Japan, where the risk of malaria is very low, and at Ehime University? The reason is that the “wheat cell-free protein synthesis system” established at Ehime University is very compatible with malaria research. Plasmodium falciparum proteins are very specific, and recombinant proteins cannot be expressed in E. coli or human cells. However, in most cases it is possible to synthesize malaria recombinant proteins in a wheat cell-free system. Therefore, I have made the best use of this system to build the world’s largest bioresource, including “4,000 Plasmodium falciparum protein arrays” and “600 Plasmodium falciparum rabbit and mouse antibody libraries. By making good use of these resources, we are revealing one after another the “key to malaria” that only we can solve.

malaria vaccine

On Wednesday, October 6, 2021, the first ever malaria vaccine was finally approved by the WHO, more than 40 years in the making, but it was found to be effective, stopping only about 30% of severe cases of malaria, and that an even more effective vaccine needs to be developed. This is a good example of the difficulty of developing a malaria vaccine. Which of the proteins synthesized from the 5,500 genes would be suitable antigens for a malaria vaccine? We decided to do the “heavy lifting” of testing them all as best we could. We tested a “library of 600 Plasmodium falciparum rabbit antibodies” and succeeded in finding a new malaria vaccine antigen called PfRipr, which we further optimized as a vaccine antigen using protein engineering and named PfRipr5. PfRipr5 has attracted much attention as a second-generation malaria vaccine candidate.

190410 Ehime Newspaper_Development of a new erythrocyte stage malaria vaccine

malaria diagnostics

If residents of endemic countries are repeatedly infected and treated, they may become infected with malaria but show no symptoms. Such humans are unaware that they are infected and become the cause of malaria epidemics. In order to efficiently find and treat such “asymptomatically infected” people, it is necessary to establish a new antibody test method. We are currently receiving sera from endemic areas around the world, including Ghana, Burkina Faso, Kenya, Papua New Guinea, and Thailand. We are searching for useful antigens for malaria diagnosis from “4,000 types of Plasmodium falciparum proteins” by using a fast and highly sensitive antibody titer assay system that we have developed independently. Our assay system is far more sensitive and reproducible than existing technologies, and we plan to use it in many more ways.

200513 Ehime Newspaper_Mitsuba fever malariaNatureMedicine

Research Features

Malaria researchers have been unable to answer questions that are easily answered in viral infections. For example, antibodies to the S protein are known to be important in new coronaviruses, but what about malaria? To which antigens are the most antibodies produced when infected with malaria? And does it contribute to the prevention of malaria infection? We are the only ones in the world who can answer these questions. Isn’t this exciting?

Research Attraction

Over the past 10 years, we have been refining our own bioresources and the specialized experimental systems to make full use of them. Now it is finally coming to fruition, and we are actively collaborating with researchers around the world. We hold nightly online meetings involving multiple groups with different languages and areas of expertise in an effort to move forward, even if only a step at a time. This “interdisciplinary” aspect of my “malaria studies” is what I find so fascinating. Wouldn’t you all like to jump across cultures, languages, and areas of specialization and interact with a variety of people? If you are interested, please contact me. Malariology is not a word I coined, but a venerable field of study that began to be used around 1900.

Future Outlook

Our research has helped us to understand the kryptonite nature of malaria. In addition, the relationship with overseas endemic countries is becoming even more robust. We intend to implement malaria vaccines and malaria diagnostics in society by making full use of molecular parasitology, protein engineering, and molecular epidemiology.

Message to those who are interested in this research

Our malaria research is attracting attention not only in Japan but also worldwide. Why don’t you join us and enjoy the view through the window that only we can open? The time is approaching for us to take revenge on malaria, which has always been the natural enemy of mankind. Let’s hit malaria in its sharpest point together.