Well-BeingWaging the fight against malaria

Malaria is one of the world's three major infectious diseases. Every year, more than 200 million people are infected and over 400,000 die, mainly in tropical and subtropical regions of Africa, Asia and Latin America. In the Department of Protozoology at Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nikon microscopes are helping researchers unravel the mechanisms of malaria infection.

Malaria - a major issue for humankind

Malaria was originally thought to be an airborne infection. That changed when British medical doctor Ronald Ross discovered malaria parasites in a mosquito by microscopic observation, and proved that malaria infection occurred when a infectee was bitten by a mosquito carrying the malaria parasite.
Malaria symptoms develop after a latency period of one to four weeks and the initial symptom is a high fever. As the disease progresses, symptoms such as impaired consciousness, renal impairment, pulmonary edema, severe anemia and multiple organ failure can occur. In the worst cases, it results in death. Special care is needed for people with weak immune systems such as infants, pregnant women and elderly people.

Anopheles mosquito sucking blood
*For test purposes. The mosquito is not carrying any parasites.
Photo courtesy of Assistant Professor Kyoko Futami, Institute of Tropical Medicine (NEKKEN), Nagasaki University
Malaria-endemic areas (brown)
Based on the WHO World Malaria Report 2017

The areas where malaria is endemic are in tropical and subtropical regions, mainly in Africa, Asia and Latin America. At present, more than 200 million people are infected every year, and over 400,000 die. Malaria was once also prevalent in Europe and North America, but it was eliminated by the introduction of water and sewerage systems, improvements in public health, and the use of insecticides and specific medicines. Japan also successfully eliminated malaria in the 1950s. However, there is still a risk that travelers infected overseas will develop symptoms after returning to Japan. In an era where many people travel regularly around the world, malaria is an urgent issue requiring international coordination, as well as countermeasures in endemic areas.
To date, the number of malaria-infected patients significantly dropped until 2015, thanks to the spraying of insecticides to control Anopheles mosquito populations, usage of mosquito nets treated with insecticide, and using specific medicines.
However, there has been no further reduction since then. Without innovative malaria controls, treatment or measures against malaria, it will be difficult to significantly reduce the incidence of malaria further.
Pharmaceutical companies and cutting-edge research facilities around the world are currently working to develop vaccines, preventive and therapeutic medicines, and diagnosis methods.

Institute of Tropical Medicine (NEKKEN) tackles tropical diseases, including malaria

One of the major centers of malaria research in Japan is the Department of Protozoology at Institute of Tropical Medicine (NEKKEN), Nagasaki University.
Originally founded in 1942 as the East Asia Research Institute of Endemics, Nagasaki Medical College, NEKKEN is engaged in research into the eradication and control of tropical diseases. The institute conducts wide-ranging activities, contributing to efforts to overcome various diseases such as Ebola hemorrhagic fever, Zika and malaria.
As well as this, NEKKEN has been cooperating with researchers in Kenya for about 50 years, and also accepts researchers, trainees and students from many countries in Africa including Kenya, Asia and Latin America.

Institute of Tropical Medicine (NEKKEN), Nagasaki University

We interviewed Professor Osamu Kaneko, M.D., Ph.D., head of the Department of Protozoology, who has been researching malaria since 1992.
One of his major areas of research is to improve understanding of the basic biology of malaria parasites, and he has been conducting multiple studies with this in mind. As he explains: "Roughly speaking, our research aims to reveal, at a molecular level, the mechanisms that malaria parasites use to propagate in the body."
The malaria parasite's lifecycle is quite complex. Dividing it broadly, there are three major stages - the "pre-erythrocytic stage" in human liver cells, the "erythrocytic stage" in erythrocytes (known as red blood cells) and the "mosquito stage" in the Anopheles mosquito.

Department of Protozoology,
Institute of Tropical Medicine (NEKKEN), Nagasaki University
Professor Osamu Kaneko, M.D., Ph.D.
"Pre-erythrocytic stage"
When an Anopheles mosquito carrying malaria parasites bites a human, the parasites are injected into the body in the form of "sporozoites" hidden in the mosquito's saliva. The sporozoites reach the liver and invade the liver cells. At this stage, some parasites enter a dormant stage and can cause a relapse in the infected person a few weeks to several years later. On the other hand, parasites growing in the liver cells proliferate into several thousands in "merozoite" form, then released into the bloodstream.
"Erythrocytic stage"
Merozoites then invade erythrocytes, where they divide into dozens of merozoites that are then released into the bloodstream and invade new erythrocytes. Parasites proliferate in the bloodstream by repeating this cycle. Some parasites in the erythrocytes differentiate into male or female gametocytes.
"Mosquito stage"
Gametocytes enter the Anopheles mosquito midgut when it sucks blood, then sexual reproduction occurs and eventually they take the form of "sporozoites" and are concealed within the mosquito's salivary glands.
(The parasite's growth during the mosquito stage is not explained in the illustration and the text.)

Thus, the malaria parasite's lifecycle is very complex and ingenious, changing location and form as it develops. And many of the details have yet to be revealed.

Microscopes help to unravel the mechanisms of malaria infection

Microscopes were indispensable for proving, in 1898, that the malaria parasite is spread by the mosquito. Even now, they are making major contributions toward unraveling the mechanisms of malaria infection.

In Professor Kaneko's laboratory, researchers analyze how malaria parasites invade erythrocytes in order to find their weaknesses, which are potential targets of intervention. The invasion process of malaria parasites is as follows: When the "merozoite" form of the parasite comes into contact with an erythrocyte, a tight junction is formed with the erythrocyte membrane while deforming erythrocytes. Then the merozoite enters the erythrocyte while forming a new membrane, called a parasitophorous vacuole membrane. During this process, various molecules released from organelles such as micronemes and rhoptries play important roles.
The erythrocytes measure about 10 µm in diameter and 2 µm in thickness, an impossibly small size to observe with the naked eye. The merozoites are even tinier than this, at about 1 µm, meaning that microscopes are indispensable for the analysis of this pathogen.
This dexterous cell invasion mechanism of the malaria parasite involves many other parasite molecules, some of which may contain the secrets for developing effective vaccines and drugs. That is why it is necessary to continue gathering information about malaria parasites at the molecular level.

Microscope images are displayed on a monitor to observe the malaria parasites.
(Kazuhide Yahata, assistant professor and research colleagues from overseas.)
At Nagasaki University-Nikon Infectious Disease Imaging Core Laboratory

Microscopes are making an important contribution in identifying the location of the parasite's molecules, and unraveling the signal transmission mechanism via phosphorylation and calcium, which triggers many biological events, such as differentiation and cell invasion.
Microscopes also greatly contribute to many research activities conducted in Kenya such as surveillance and analysis of malaria infection and vector mosquitos, as well as drug resistance tests for malaria parasites collected through these activities.

Malaria surveillance at Ungoi area, Kenya
Dr. Masatsugu Kimura, Graduate School of Medicine, Osaka City University
Malaria Surveillance at Mfangano Island, Kenya
Dr. Wataru Kagaya, Graduate School of Medicine, Osaka City University
Teleconference with Kenyan researchers
Researchers from Kenya and Ghana join the discussions

Professor Kaneko concludes the interview by talking passionately about his research: "If we can understand the weaknesses of the malaria parasite in a biological relationship, we believe we can contribute to the development and improvement of effective vaccines, drugs and diagnostic methods. I also hope we can clarify the mechanisms of drug resistance of the parasites and use this knowledge for treatment. I will be very glad if our research can contribute to the health and well-being of those who are suffering from this difficult-to-eradicate disease."

Researchers are working hand in hand with many people around the world in the fight against malaria. We hope Nikon's microscopes will help them in that fight.

We also spoke with two of Professor Kaneko's colleagues.

Kazuhide Yahata, Ph.D., Assistant Professor,
Department of Protozoology, Institute of Tropical Medicine, Nagasaki University

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My role is to give advice to the members of our team in the laboratory so that everyone can work together. I also provide support to researchers, trainees and students from Kenya and other countries.

Edwin Too (trainee from Kenya)

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In my country, many people die every year because of malaria, especially young children and young pregnant women. I want to learn as much as I possibly can at the Institute of Tropical Medicine, so I can help my country to reduce such tragedies.