Stealth and sabotage

15/07/15
By Abigail Perrin

Parasites invade host blood cells, causing major disease and shielding themselves from the immune system. Credit: David Gregory&Debbie Marshall, Wellcome Images

Parasites invade host blood cells, causing major disease whilst shielding themselves from the immune system.
Credit: D. Gregory and D. Marshall, Wellcome Images

Plasmodium parasites – the causative agents of malaria – have infected humans for tens of thousands of years. Despite these parasites being some of our oldest enemies, we are surprisingly badly armed to defeat them.

People who have had malaria before are by no means immune to the disease in the future. Even those who do acquire resistance to symptoms often still carry parasites in their blood. New drugs and a vaccine are highly sought-after in the fight against Plasmodium parasites, but we need a better understanding of the relationship between the parasite and the immune response to ensure that these weapons will be effective.

Proteins are important mediators of parasite functions, and they often carry out these functions by means of interacting with the proteins of their human host. We know of a number of host-parasite protein-protein interactions that are critical to the disease process. For instance an interaction between a parasite protein called RH5 and human Basigin (found on the red blood cell surface) is essential to allow the parasite to invade host blood cells. Here they cause the major disease symptoms whilst shielding themselves from the surveillance of the immune system.

The parasite’s intracellular hideout certainly helps it evade detection, but does not entirely account for our frequent failure to eliminate parasites from our blood. By studying Plasmodium proteins we’ve found out a number of ways that the parasite fools the immune system but it is likely that there are many more mechanisms still to be discovered.

In the Cell Surface Signalling Laboratory at the Wellcome Trust Sanger Institute we are now able to make a library of synthetic proteins representing those on the surface of, and released by, Plasmodium parasites. Using a specialised protein interaction detection assay, known as AVEXIS we’ve used these proteins to discover two host-parasite interactions that help the parasite gain entry into red blood cells. In my work, I used these proteins to look for ways in which the parasite interacts with the immune system.

I found that proteins from the parasite MSP7 family bind to P-selectin, a human protein with an important role in the human immune response.

P-selectin is present on the walls of blood vessels during infections and one of its most important roles is to bind to white blood cells and promote their antimicrobial activities. This function is dependent on a particular part of the P-selectin protein that attaches to sugars on the surface of the white blood cell. I showed that MSP7 proteins could prevent the interactions of P-selectin with these sugars, which implies that MSP7 could be acting to prevent the activation of white blood cells that could otherwise kill parasites.

Though further investigation is needed to determine the importance of MSP7/selectin interactions in real-life infections, they could help us uncover a new mechanism in P. falciparum’s repertoire of strategies to outsmart the immune response.

Abigail Perrin was a PhD student under the supervision of Dr Gavin Wright, studying host-parasite protein-protein interactions in malaria.

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2 thoughts on “Stealth and sabotage

  1. Excellent post, Abigail. What sort of approaches will you be looking at in the future? What sort of impact do you think that advances in this area will have on the people and communities in areas at risk from malaria?

    • With respect to these particular interactions the most important questions are ‘how important are they to the parasite?’ and ‘how do they affect the infected host?’. We’ve got some evidence from parasites that do not make MSP7 and mice without P-selectin that these proteins, and perhaps therefore their interaction, do change the course of disease; MSP7-deficient parasites are slightly less deadly in some systems, and mice without P-selectin do not get cerebral malaria). In general, the interactions between host-and parasite are good targets for potential drug and vaccines, one idea being that if you can block them you can disrupt the processes that cause disease. This is the basis for a couple of antiviral drugs. As for malaria, vaccines/drugs targeting the RH5/Basigin interaction are being investigated. So in the future, I think that understanding these interactions will help us rationally design the most effective prevention and treatment measures possible.

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