BioWorld International Correspondent
LONDON—New antimalarial drugs that will stop the infection before it has even begun could flow from the discovery that infection of liver cells by the malarial parasite follows activation of a cell-surface receptor.
Maria Mota, group leader in malaria cell biology at the Instituto Gulbenkian de Ciencia in Oeiras, Portugal, told BioWorld International that, coincidentally, several major pharmaceutical companies have already begun to develop drugs that will inhibit that type of receptor because of its oncogenic effects when activated.
She said: "We are already in contact with some of these companies and hope that such inhibitors may be able to stop the initial infection. Even if such an inhibitor is not totally effective, it would still have a big effect in reducing the symptoms and the spread of the parasite."
One strategy, she suggested, might be to supply the inhibitor in certain foods.
Mota's collaborators include teams at New York University School of Medicine, the University of Torino School of Medicine in Italy, and the Universidad Autonoma de Madrid in Spain. The group reported their findings in Nature Medicine (published online Oct. 12, 2003) titled "Hepatocyte growth factor and its receptor are required for malaria infection."
Malaria is caused by the bite of a mosquito infected by parasites of the genus Plasmodium. The parasites, which are called sporozoites at that stage of the infection, migrate to the liver and are only able to infect hepatocytes (liver cells). Within 7 days, each sporozoite that infects a hepatocyte has divided to form 30,000 new parasites, now called merozoites. Those are capable of infecting only red blood cells. Each merozoite that infects a red blood cell again divides, this time taking only 48 hours, into 15 to 20 new merozoites. It is the synchronous release of new generations of parasites from the red blood cells that causes the anemia and intermittent fever typical of malaria.
However, Mota and her colleagues had noticed that rather than infecting the first hepatocyte they encounter, the sporozoites travel through several hepatocytes, damaging them, before settling on one to infect.
Mota said: "We knew from work on cell wounding that this can cause molecules including growth factors to be released, which can signal to neighboring cells." They hypothesized that perhaps that process made the surrounding cells more susceptible to infection.
In fact, their experiments, carried out on murine liver cells, showed that the damaged cells are stimulated to start producing hepatocyte growth factor (HGF). Secretion of HGF does not happen immediately, but begins after a few minutes and continues for several hours. The growth factor, in turn, activates the HGF receptor, which is a tyrosine kinase receptor called MET.
Additional investigations showed that signaling by MET, as a result of activation by HGF, was essential for Plasmodium sporozoites to infect hepatocytes. Furthermore, such signaling was not essential for the sporozoites to get into the cells, but it was needed if the parasites were to continue to develop after gaining entry.
Mota and her colleagues also found that, shortly after HGF/MET signaling, the actin cytoskeleton of the infected cells became reorganized. Adding a drug that abolishes the movement of the cytoskeleton had the effect of completely preventing development of the sporozoites.
"We have no idea why the cytoskeleton is important here," Mota said. "However, the cytoskeleton is needed for nutrients to travel around the cell, so it could be that the parasite needs it to bring nutrients for its own development."
Apart from finding drugs that can block HGF/MET signaling, the team also wants to find out if sporozoites use any other mechanism for entering cells. Mota pointed out that the finding emphasizes that many factors in the host are important for parasite development. "So we want to take a more general approach to finding out what is going on in parasitized cells, by doing proteomics to see how the proteins made in these cells are different to those made in uninfected cells," Mota said.
The team also speculates that their finding can explain some recent observations about malaria. Writing in Nature Medicine, they conclude: "The requirement of MET signaling for malaria infection has important clinical implications. It may explain why severe malaria cases are more frequent in hepatitis B virus carriers, who have elevated HGF levels, than in matched controls." They add that the recently described beneficial effect of vitamin A in malaria infection may be partly due to inhibition of HGF production by retinoic acid, which is a metabolite of vitamin A.