Targeting the malaria parasite’s ability to make an iron-containing molecule, haem, might help create a vaccine against the disease and also lead to novel drug therapies for blocking infection and transmission, according to research from a team of Indian scientists that was published recently in PLOS Pathogens.
In the course of its complex life cycle, the parasite is able to access haem when it infects red blood cells and gobbles up the haemoglobin those cells contain. Haemoglobin is the molecule that makes it possible for red cells to transport oxygen around the body.
Work carried out two decades back at G. Padmanabhan’s laboratory at the Indian Institute of Science (IISc) in Bangalore had led to the discovery that nevertheless the human malaria parasite could also synthesise haem. The enzymes involved in the complex, multi-step process used by the parasite for doing so were subsequently worked out.
Now, experiments carried out by a team of scientists at the IISc and the National Institute of Malaria Research have shown that having the capability to synthesise haem was “absolutely essential” for the parasite’s development in mosquitoes as well as in early stages of infection when it invades the liver.
When the single-celled parasite consumes haemoglobin found in red cells, the large amounts of haem generated as a consequence is toxic to the organism. It overcomes the problem by turning haem into an insoluble pigment, haemozoin. However, the parasite needs haem for iron-containing proteins, known as cytochromes, that are essential for its own energy production.
“The question arises whether the parasite depends on de novo haem biosynthesis or haem from haemoglobin or a combination of both to make mitochondrial cytochromes,” observed Viswanathan Arun Nagaraj, a Ramanujan Fellow at IISc, and his colleagues in the paper.
To help answer that question, the scientists turned to Plasmodium berghei, a malaria parasite that infects mice. The P. berghei was genetically modified so that two genes for enzymes the parasite required to synthesise haem were knocked out. The scientists were able to show that while much of the haem from haemoglobin breakdown ended up as haemozoin, some of it was also incorporated into the parasite's cytochromes.
Then, through experiments using the human malaria parasite, Plasmodium falciparum, they found that haem synthesised by the parasite while it was in red cells went into cytochromes as well as the haemozoin pigment.
It may be that the ability of synthesise haem was critical to the parasite in situations where it could not get access to the host's haem, such as when an infected individual had sickle cell anaemia, said Prof. Padmanabhan, who is a co-author of the paper.
The scientists found “clear proof ” that haem synthesis was vital for the parasite's development in mosquitoes. Parasites that were unable to make haem did not give rise to its infectious form, known as sporozoites, in the insect’s salivary glands.
Genetically engineered P. berghei, which had one gene for haem synthesis knocked out, could make haem and produce sporozoites when the missing intermediate molecule was supplied. However, those sporozoites, lacking the ability to generate haem, were unable to infect mice.
Knocking out genes for haem synthesis could be a way to produce genetically attenuated sporozoites that might serve as a vaccine candidate for malaria, according to Dr. Nagaraj. Recently published research had shown that attenuated sporozoites could be an extremely effective vaccine against malaria.