Wednesday, 27 July 2011

MALARIA: The fight with immunity

27 Jul, 2011 : Michael Regnier
A pair of wrestlers; image credit: Wellcome Images Wellcome Images;A pair of wrestlers, 19th century watercolour

Evolution is a wonderful thing. Not least among its achievements is the human immune system, which has evolved complex mechanisms and cell-types to try and keep our bodies free from infections and parasitic invasions.
Unfortunately, evolution works for both sides: the threats to our bodies are constantly updating and improving themselves to get round our immune defences.
Take malaria, for example. Pregnant women are particularly susceptible to malaria infection and it has a high risk of disease and death for both mother and fetus. Research published this month has revealed a new way in which malaria evades the immune system in pregnant women. It is just the latest round in the long evolutionary contest between humans and malaria.

Malaria 0 – 0 Humans
The parasite that causes the most severe forms of malaria is called Plasmodium falciparum. When it infects us – through a mosquito bite, for example – it doesn’t just hang around in our blood waiting for our immune system to find and destroy it. Instead, it stows aboard our red blood cells and uses them to move through the body.

Malaria 1 – 0 Humans
In order to hijack our cells effectively, P falciparum has to force each red blood cell it infects to make certain non-human proteins, some of which appear on the cell’s surface. Our immune system can see these abnormal proteins and recognise them as a sign of trouble.
Our immune system identifies intruders by using antibodies as scouts. There are five types of antibodies – immunoglobulins A, D, E, G and M – that have slightly different characteristics and roles. For example, immunoglobulin G (IgG) is the most important for providing immunity against invaders but takes time to build up sufficient numbers. Immunoglobulin M (IgM) provides an early defence by stimulating another part of the immune system before the IgG element kicks in.
Having malarial proteins on their surface makes infected red blood cells vulnerable: IgG antibodies will bind to these proteins, stimulating the rest of the immune system to dispose of the infected cells.

Malaria 1 – 1 Humans
In addition, our bodies will make more of this particular IgG so that we are better prepared to recognise and deal with future infections.

Malaria 1 – 2 Humans
Of course, P falciparum has an answer. It frequently changes the surface proteins it makes in infected cells. Often it tweaks them just enough to make them unrecognisable to our antibodies, which puts the immune system right back to square one.
Even smarter, from the parasite’s point of view, is that the proteins it expresses on the red blood cells include some that direct the infected cells to leave the blood and hide in other tissues.
In pregnant women, P falciparum produces a protein called VAR2CSA that selectively binds to chondroitin sulphate A (CSA) in the placenta. As a result, infected cells build up in the placenta, which causes life-threatening inflammation.

Malaria 2 – 2 Humans

IgM binding to a domain of the VAR2CSA protein IgM binding to a domain of the VAR2CSA protein
Professor Richard J Pleass

Our IgG antibodies are still capable of recognising VAR2CSA as a foreign protein, though. At least, they would be if P falciparum didn’t have one more trick up its sleeve, as revealed this month by a group of researchers based in Denmark, Ghana and Liverpool.
The VAR2CSA protein is not just a target of IgG. It can also be bound to by IgM. Unfortunately, IgM doesn’t bind to VAR2CSA strongly enough to elicit an immune response. Worse still is that it physically blocks IgG from binding to VAR2CSA, effectively shielding the malaria protein from the rest of the immune system.

Malaria 3 – 2 Humans
Malaria seems to have this sewn up. But it’s certainly not all over and we humans have one more thing in our favour: medical research.

Half-time team talk…
The researchers who showed how P falciparum uses IgM as a shield also showed that it leaves one vital part of VAR2CSA exposed: the bit that binds to CSA. The authors suggest that a vaccine could be developed to prime the immune system to recognise this Achilles heel.
At a stroke, this would prevent P falciparum from accumulating in the placenta as well as expose infected cells to the full force of the immune system. It would change the game in placental malaria and perhaps put us ahead in the evolutionary contest.

Barfod, L., Dalgaard, M., Pleman, S., Ofori, M., Pleass, R., & Hviid, L. (2011). Evasion of immunity to Plasmodium falciparum malaria by IgM masking of protective IgG epitopes in infected erythrocyte surface-exposed PfEMP1 Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1103708108

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