Thursday, May 21, 2015

Gra17 And Gra23 Proteins As New Target For Anti-Malaria Drugs

Gra17 And Gra23 Proteins As New Target For Anti-Malaria Drugs

In a paper published in Cell Host and Microbe, the researchers describe how they identified novel drug targets while studying the way in which the parasites Toxoplasma gondii (which causes toxoplasmosis), and Plasmodium, (which causes malaria), access vital nutrients from their host cells.

Pathogens that cause malaria and tuberculosis spend a large portion of their life inside specially built compartments within their host cells. These compartments, termed as “parasitophorous vacuoles,” separate the host cytoplasm and the parasite by a membrane, and thereby protect the parasites from the host cell’s defenses. These "vacuoles" appeared to be designed in such a manner that its membrane acts as a barrier between the parasite and the host cell. This makes it more difficult for the parasite to release proteins involved in the transformation of the host cell beyond the membrane in order to spread the disease, and for the pathogen to gain access to vital nutrients.

Previous research has shown that the vacuoles are selectively permeable to small molecules, allowing certain nutrients to pass through pores in the membrane. But until now, no one has been able to determine the molecular makeup of these pores, and how they are formed.

Researchers used the most basic knowledge of survival to solve this riddle. A parasite by definition will hunt for certain key nutrients from their host. So it will evolve some mechanism to overcome these “vacuoles” membrane issues to gain access to these nutrients. The researchers discovered two proteins namely GRA17 and GRA23, secreted by the parasite Toxoplasma, which are responsible for forming these pores in the vacuole.  Though it was found by an accident (as all good researches have been ), while investigating how the parasites are able to release their own proteins out into the host cell beyond the vacuole membrane after invasion. Similar research into how the related Plasmodium pathogen performs this trick had identified a so-called “protein export complex” that transports encoded proteins from the parasite into its host red blood cell, which transforms these red blood cells in a way that is vital to the spread of malaria.

Moreover, researchers identified proteins secreted by Toxoplasma that appeared to be homologues, or of shared ancestry to, this protein export complex in Plasmodium.

In the next step, researchers planned experiments to find out what these proteins do to help the parasite survive. When researchers stopped these proteins from functioning, they found it made no difference to the export of proteins from the parasite beyond the vacuole. This meant that these proteins are involved in something more important that protein export, which might be small molecule transfer (as in survival important). So, in step two researchers added dyes to the host cell, and again knocked out the two proteins, the researchers found that it prevented the dyes flowing into the vacuole. More significantly though, when the researchers expressed a Plasmodium export complex gene in the modified Toxoplasma, they found that the dyes were able to flow into the vacuole once again, suggesting that this small-molecule transport function had been restored.

The authors summed up their works in these important statements:

1. Crucially, since these proteins are only found in the parasite phylum Apicomplexa, to which both Toxoplasma and Plasmodium belong, they could be used as a drug target against the diseases.

2. This is a really strong potential drug target for restricting the access of these parasites to a set of nutrients.

3. In addition to malaria, the technique could also be used to target the parasite Eimeria, which affects cattle and poultry, among other animals, and therefore has a huge economic cost.

Article Citation: Gold, D. A.; et. al. The Toxoplasma Dense Granule Proteins GRA17 and GRA23 Mediate the Movement of Small Molecules between the Host and the Parasitophorous Vacuole. Cell Host Microbe 2015, 17(5), 642-652.