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Malaria stripped of its deadly disguises

作者:仰唏    发布时间:2019-02-28 03:09:02    

By Philip Cohen WHEN malaria kills, it does so by slowly depriving the brain of its blood supply. Yet despite its long residence in the body, the malaria parasite somehow avoids destruction by the immune system. Researchers in the US have now identified the genes that underlie malaria’s deadly effects, and have found that they also hold the key to its ability to evade the immune system. The deadliest form of malaria is caused by the single-celled parasite Plasmodium falciparum, which multiplies inside red blood cells. For several years, biologists have known that P. falciparum’s murderous ways are due to a protein dubbed PfEMP1. This migrates to the surface of infected cells and anchors them to the walls of capillaries near organs, including the brain. Clusters of infected cells form clots, blocking the flow of blood. The puzzle, however, has been the failure of the immune system to recognise the alien PfEMP1 protein and destroy the infected cells. One possible explanation is that there is not one PfEMP1 protein but many, each encoded by a different gene. The parasite could then keep one step ahead of the immune system by switching from one gene to another. But researchers have failed to work out the complete amino acid sequence of any PfEMP1 protein, let alone find any PfEMP1 genes. Now two American research teams have revealed the identity of the PfEMP1 genes. And with the help of other researchers in the US and Britain, they have vindicated the gene-switching theory. “When we finally found the genes, it was total serendipity,” admits Thomas Wellems of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland. Wellems’s team was studying chromosome 7 of P. falciparum in search of a gene that renders malaria resistant to the drug chloroquine, when they came across a cluster of five related genetic sequences. When the researchers looked elsewhere in the parasite’s genome, they found that similar genes showed up on most of P. falciparum’s 14 chromosomes (Cell, vol 82, p 89). The function of these new genes was initially a mystery. But another group led by Russell Howard of the Affymax Research Institute in Santa Clara, California, showed that Wellems had stumbled across the PfEMP1 genes. They genetically engineered bacteria to produce P. falciparum proteins by adding fragments of the parasite’s DNA and exposed these to anti-PfEMP1 antibodies. As Howard’s team reports in the same issue of Cell (vol 82, p 77), the bacteria targeted by these antibodies carried P. falciparum genetic sequences that are similar to those found by Wellems’s team. These genes are incredibly abundant – each malaria parasite has up to 150. This fits perfectly with the gene-switching hypothesis, as such a large number of genes would provide the multitude of disguises that P. falciparum needs. Evidence that supports this idea has been found by researchers led by Chris Newbold of the Institute of Molecular Medicine in Oxford, working with Louis Miller and his colleagues at NIAID. They used Wellems’s sequences to show that each P. falciparum cell produces one PfEMP1 protein at any given time, but also found that the parasite frequently switches to another gene to produce a different protein. Newbold and Miller also describe their results in the current issue of Cell (vol 82, p 101). Now that the sequence of the PfEMP1 genes and proteins is known, it may be possible to screen for drugs to block the production of the proteins, and so prevent infected cells sticking to capillaries. The extreme diversity of the PfEMP1 genes and proteins may be a problem, however, because a drug that disables one protein might not work so well against another. Wellems estimates that there are millions of PfEMP1 genes in the world’s P. falciparum population. A better approach, however, may be to develop drugs against the PfEMP1 gene-switching mechanism, which presumably varies little from parasite to parasite. If this were disabled, then the parasite would produce just one PfEMP1 protein,

 

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