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Science initiated in Nottingham has helped to form the foundation for the latest breakthrough in the global fight against malaria.
Researchers in the University of Nottingham’s School of Life Sciences were responsible for the identification of the molecular switches that control the three key stages of the malaria parasite’s life cycle – work which has underpinned a new discovery about the way in which the growth of the parasite is controlled.
Now, a team of international scientists led by Portuguese academics has discovered that one of the proteins identified by the Nottingham experts plays a vital role in modulating the parasite’s rate of replication by sensing the nutritional status of its host.
The results of the study, published in the journal Nature, show that this may ultimately dictate the outcome of a malaria infection: survival or death.
Rita Tewari, Professor of Parasite Cell Biology in the University’s School of Life Sciences said: “This work comes as a result of major work which we undertook to further our understanding of how the protein signalling molecules called kinases control the malaria parasite development in the host body and the gut of the mosquito.
“As a result of our research, we produced a big resource of proteins called kinases and enzymes which work in tandem with them called phosphatases, which are very good potential targets for drugs. This is a valuable resource for the scientific community working on malaria.”
Biggest killer
Malaria is the world’s biggest killer - in 2015 alone, there were 296 million cases of malaria worldwide, resulting in an estimated 731,000 deaths. The tropical disease is caused by the parasite Plasmodium and is spread through the bite of an infected female mosquito.
Protein kinases and phosphatases are crucial for many stages of the malaria parasite lifecycle. They are two families of enzymes that play crucial roles in regulating many cell processes – the ‘yin and yang’ of cell development.
The latest published research centres on the role of one kinase called pbKIN, which allows the infectious agent responsible for malaria, the Plasmodium parasite, to sense how many calories are being taken in by the host and tailor its replication accordingly.
Plasmodium parasites reproduce inside red blood cells every 48 hours but the study has shown for the first time that the parasite’s rate of replication depends on the calories ingested by the host - using mouse models of malaria infection, the study showed that mice who ate 30 per cent fewer calories had a significantly lower parasite infection.
Maria M. Mota from Instituto de Medicina Molecular in Lisbon, who led the research, said: “This finding alters our understanding of the dynamics of malaria infections in the field and might be highly relevant facing the alarming trend of global increased overweight verses underweight populations, including in malaria endemic regions.”
Two possibilities explain the finding – either the parasite is actively adapting when changed to a host with a lower calorie intake, or instead was struggling to replicate due to the fact that some key nutrients were missing.
Researchers controlled the food intake of mice before infection with different Plasmodium parasites and studied their response. They found that parasites without pbKIN seemed unable to sense nutrient availability and replicated at the same speed, regardless of the food available to the mice.
Parasite lifecycle
Dr Oliver Billker, a collaborator on the research from the Wellcome Trust Sanger Institute, said: “This is the first time that anyone has seen that a parasite can actively restrict its growth to the environment and completely changes the way we look at parasite growth. While future research is still necessary to understand the full extent of these findings, it may well have implications not just for malaria, but also for other infectious diseases.”
A better understanding of this system may help researchers find ways to trick the parasite into slowing its replication to make it easier to control.
The ultimate aim of malaria research is to disrupt the three main stages of the parasite’s lifecycle - whether it be in the liver, in the mosquito gut or in the blood.
Professor Tewari’s laboratory is working on understanding which signals are needed for the parasite to divide and reproduce.
Professor Tewari added: “If we can understand the unique molecular machinery that allows the parasite to replicate then we can find strategies to prevent it. Parasite proliferation is more like an abnormal cancer cell in which the cell divides many times, very quickly and without many checks.
“We have shown in the past that many proteins called cyclins or usual switches like phosphatases that are in present humans cells and regulate cell division are either absent or very different in malaria parasite cell.That means that the Plasmodium – the malaria – is not using the usual machinery which other normal cells use.
“Now we are trying to understand what the parasite does differently that is not present in the host, the human cell, as that would be the best target for drugs. If we can kill the parasite using those targets, then it won’t affect the human and would reduce side effects of malarial medication.”
The Nottingham team continues to study the molecules controlling cell proliferation of parasites and has recently been awarded around £900,000 grant funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and the Medical Research Council (MRC).
The latest research, Nutrient sensing modulates malaria parasite virulence, is published in the journal Nature and is a collaboration between scientists at Instituto de Medicina Molecular and Instituto Gulbenkian de Ciência in Portugal, Institut Pasteur in Paris, the Wellcome Trust Sanger Institute, University of Nottingham in the UK and The Pennsylvania State University in the US.
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