Human iPSCs Spur Malaria Research

Human liver cells derived from induced pluripotent stem cells have helped scientists studied an elusive stage of the Plasmodium vivax parasite’s life cycle.

AsianScientist (Aug. 20, 2020) – An international team of researchers has developed a method of studying a critical life stage in the common but poorly understood Plasmodium vivax malaria parasite. Their approach, described in Malaria Journal involves feeding mosquitoes with the blood of infected patients and culturing the parasites in patient-derived induced pluripotent stem cells (iPSCs).

Although P. vivax is responsible for around 7.5 million malaria cases worldwide, there is only one licensed drug to treat the liver stage of the parasite’s life cycle, 8-aminoquinoline primaquine. Furthermore, primaquine has many side effects and cannot be used in pregnant women and infants.

“The P. vivax malaria parasite can stay dormant in a person’s liver cells up to years following infection, leading to clinical relapses once the parasite is reactivated,” said Professor Kouichi Hasegawa of Kyoto University.

P. vivax is particularly hard to treat because it undergoes a dormant liver stage which makes it resistant to most existing drugs. To get around this problem, Hasegawa and colleagues in Japan, India and Switzerland developed a system for breeding mature P. vivax parasites, culturing human liver cells from iPSCs and infecting the cells with the parasites.

The researchers first bred Anopheles stephensi mosquitoes in an insectarium in India. Female mosquitos were then fed with blood specifically from Indian patients with P. vivax infection. Two weeks later, mature sporozoites—the infective stage of the malaria parasite—were extracted from the mosquitos’ salivary glands and added to liver cells cultured in a petri dish.

The scientists tested different types of cultured liver cells to try to find cells that would be infected by lots of parasites like in the human body. Researchers have already tried using cells taken liver biopsies and of various liver cancer cell lines. So far, none have led to large infections.

Instead, the team tried using three types of stem cells that were turned into liver cells in the lab. Notably, they took blood cells from malaria-infected patients, coaxed them into pluripotent stem cells, and then guided those to become liver cells, in the hopes that they would be genetically more susceptible to malaria infection. However, the cells were only mildly infected when exposed to the parasite sporozoites.

A low infection rate means the liver cells cannot be used for testing many different anti-malaria compounds at once. However, the cells could be used to test if an anti-malaria compound would work for a specific patient. This could improve individualized treatment for patients, the authors said.

The protocol also allowed the scientists to study one of the many aspects of parasite liver infection. They observed the malaria protein UIS4 interacting with the human protein LC3, which protected the parasite from destruction. This demonstrates their approach can be used to further investigate this important stage in the P. vivax life cycle.

“Our study provides a proof-of-concept for detecting P. vivax infection in liver cells and provides the first characterization of this infectious stage that we know of in an endemic region in India, home to the highest burden of vivax malaria worldwide,” said Hasegawa.

The article can be found at: Subramani et al. (2020) Plasmodium vivax Liver Stage Assay Platforms Using Indian Clinical Isolates.


Source: Kyoto University; Photo: Erop Kamelev/Unsplash.
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