Discovery of key molecules involved in severe malaria

Malaria*1 is one of three major infectious diseases*2 affecting approximately 300 million people every year, accounting for about 500,000 deaths, but effective vaccine development has not been successful. Among malaria parasites infecting humans, Plasmodium falciparum (P. falciparum)*3 causes especially severe disease. In addition, acquired immunity to malaria is inefficient, even after repeated exposures to P. falciparum, but the immune regulatory mechanisms used by P. falciparum remain largely unclear. Therefore, malaria parasites appear to have a mechanism to escape our immune system.

A research group led by Fumiji Saito, Kouyuki Hirayasu, Hisashi Arase at Osaka University found that proteins called RIFIN expressed on erythrocytes infected with P. falciparum help the parasite to suppress the host immune response, causing severe malaria (Fig. 1). These findings are expected to contribute to the development of effective vaccines and therapeutic drugs against malaria.

Malaria parasites infect mainly erythrocytes in the host and proliferate within infected erythrocytes. The team found that proteins called RIFIN*4 expressed on P falciparum-infected erythrocytes bind to a host inhibitory receptor LILRB1*5. Furthermore, RIFIN suppresses the immune response to malaria, resulting in severe complications of malaria.

This research disclosed for the first time in the world that P. falciparum has a new mechanism to suppress the host immune response by using an inhibitory receptor, contributing to the pathogenesis of severe malaria. The results of this research are expected to greatly contribute to the development of therapeutic drug and vaccine against malaria.

*1 Malaria
Infectious diseases caused by malaria parasites

*2 Three major infectious diseases
Malaria, tuberculosis, and HIV/AIDS

*3 Plasmodium falciparum
Malaria parasites infecting humans, and causing the most severe complications of malaria

RIFIN proteins are encoded by the rif (repetitive interspersed family) genes of P. falciparum. There are about 150 rif genes per parasite genome. However, their functions have been still unclear.

One of the immune inhibitory receptors that suppress the activation of immune cells and prevent autoimmune responses by recognizing self-molecules like major histocompatibility complex (MHC) class I. Human cytomegalovirus is also known to have a viral MHC class I-like molecule (UL18) that suppresses the immune response via LILRB1 for immune escape.

‘Open Science’ Paves New Pathway To Develop Malaria Drugs

Malaria remains one of the world’s leading causes of mortality in developing countries. Last year alone, it killed more than 400,000 people, mostly young children. This week in ACS Central Science, an international consortium of researchers unveils the mechanics and findings of a unique “open science” project for malaria drug discovery that has been five years in the making.

The current gold standard antimalarial treatments are based on artemisinin, a compound developed in the 1970s in China, combined with a partner drug. Yet, resistance to artemisinin and its partners has already emerged in some parts of the world. If the resistance spreads, there are no viable replacement treatments. Given the lack of commercial incentive for industry to develop drugs for neglected diseases such as malaria, and because academic researchers often lack resources to move compounds forward, there is a clear need for new approaches. In response, Matthew Todd from the University of Sydney together with the not-for-profit research and development organization Medicines for Malaria Venture proposed an “open source” solution akin to the open source concept used in software development.

More than 50 researchers from 21 organizations in eight countries added their research to the project, which started with a large set of potential drug molecules made public by the company GlaxoSmithKline. Anyone willing to contribute — anywhere in the world — was welcome to share data and collaborate by adding comments to an electronic notebook as part of the Open Source Malaria Consortium. Some scientists designed and synthesized new generations of the antimalarial compounds; others ran assays and interpreted results. Several rounds of research were conducted, addressing water solubility and structural issues, with all the data being made public in real time. A wide array of scientists, from professors to undergraduates, participated by choice, agreeing that no one would individually seek patents to protect their contributions. The authors note that the current results, while promising, are merely the beginning of the story. They continue to welcome additional contributions, also researched openly and collaboratively.

How Do You Kill a Malaria Parasite? Clog It with Cholesterol

Drexel University scientists have discovered an unusual mechanism for how two new antimalarial drugs operate: They give the parasite’s skin a boost in cholesterol, making it unable to traverse the narrow labyrinths of the human bloodstream. The drugs also seem to trick the parasite into reproducing prematurely.

Malaria is a mosquito-borne disease caused by Plasmodium parasites. After a person is bitten, the parasite invades the victim’s red blood cells. There, it eventually divides into daughter parasites, which continue to destroy each red blood cell they infect.

There are several drugs under development that interrupt this life cycle, including a class of compounds discovered in 2014 by Akhil Vaidya, PhD, a professor at Drexel University College of Medicine. In their 2014 study, Vaidya and his research team found that these drugs increase levels of sodium within the parasites’ cells, causing them to swell and erupt.

However, in a new study, published recently in PLOS Pathogens, the researchers have revealed that this sodium increase actually triggers a more complex cascade of events, eventually changing the parasite’s outer membrane and also tricking it into early reproduction, which renders the parasite inert.

“Nobody suspected something like this to be the mode of action,” said Vaidya, who also directs Drexel’s Center for Molecular Parasitology. “The mechanism is a lot more complicated and interesting than we originally thought.”

In this study, the scientists focused on two small-molecule drugs, one of which is undergoing clinical trials. Despite very different molecular structures, both drugs initially increase sodium within the parasite and subsequently kill the pathogen. Until now, scientists have not understood why the increase in sodium concentration leads to the malaria parasite’s demise.

To explore this question, the researchers first tested the properties of the Plasmodium plasma membrane — or the parasite’s outer skin — before and after exposure to antimalarial drugs. The Plasmodium membrane is unusual, because it contains very low levels of cholesterol, a major lipid component of most other membranes, including those of human red blood cells.

The Drexel scientists hypothesized that the low cholesterol content permits greater flexibility for the parasite to travel through the human bloodstream and to withstand the stress of blood circulation. They propose that the sodium increase, caused by the antimalarial drugs, somehow interferes with that elasticity.

The researchers used a cholesterol-dependent detergent to detect the presence of lipids in the parasite membrane. They found that indeed both drug treatments appeared to add a significant amount of cholesterol to the Plasmodium plasma membrane.

“We believe that the cholesterol makes the parasite rigid, and then the parasite can no longer pass through very small spaces in the bloodstream,” Vaidya said, adding that the parasite cannot continue its lifecycle if it cannot enter red blood cells.

Just two hours after treatment, the scientists also saw that many of the parasites showed fragmented nuclei and interior membranes, which are the precursors to cell division. But these changes happened without any sign that the parasite’s genome had multiplied — a step that is necessary for a cell to divide and survive.

The researchers hypothesize that sodium influx is a normal step during the malaria parasite’s division. The antimalarial drugs prematurely induce this signaling event, and the parasite begins dividing before it should.

“The parasite is not ready to divide yet, so it can not survive. It is like premature delivery of an infant,” Vaidya said. “This whole cascade of events is triggered by these drug treatments.”

Malaria is the world’s deadliest parasitic disease. It kills more than 300,000 people per year, according to the World Health Organization, and affects up to 300 million.

One of the biggest challenges for treating malaria is drug resistance. The drugs that are currently available are quickly losing their potency, so researchers are scrambling to develop stronger treatments.

By understanding exactly how new drug candidates stop malaria, Vaidya and his team aim to reveal more about the parasite’s vulnerabilities. This, they hope, will eventually lead to the creation of more effective drugs against the disease. Vaidya noted that the best defense against malaria will always be a combination of treatments.