MALARIA: The fight with immunity

27 Jul, 2011 : Michael Regnier

 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

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.

Reference
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

http://wellcometrust.wordpress.com/2011/07/27/the-long-game-fighting-malaria/#more-6076

MALARIA: Intermittent Treatment to Prevent Pregnancy Malaria Does Not Confer Benefit in an Area of Widespread Drug Resistance

Whitney E. Harrington et al. 

Intermittent Treatment to Prevent Pregnancy Malaria Does Not Confer Benefit in an Area of Widespread Drug Resistance

Millions of African women receive sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment during pregnancy (IPTp) to avoid poor outcomes that result from malaria. However, parasites resistant to SP are widespread in parts of Africa, and IPTp may perversely exacerbate placental infections that contain SP-resistant parasites.

Methods. The study used a cross-sectional design. We determined IPTp use in a delivery cohort of 880 pregnant women in Muheza, Tanzania, by report and by plasma sulfa measurements, and we examined its effects on maternal and fetal delivery outcomes.Results. In the overall cohort, IPTp was not associated with decreased odds of placental malaria or with increased mean maternal hemoglobin or mean birth weight. Unexpectedly, IPTp was associated with decreased cord hemoglobin level and increased risk of fetal anemia, which may be related to in utero SP exposure.

Conclusions. IPTp does not improve overall pregnancy outcomes in Muheza, Tanzania, where SP-resistant parasites predominate and may increase the odds of fetal anemia. As parasite resistance increases in a community, the overall effect of IPTp may transition from net benefit to neutral or net harm.

http://cid.oxfordjournals.org/content/53/3/224.abstract

MALARIA: Malaria parasites use camouflage to trick immune defences of pregnant women

Researchers from Rigshospitalet – Copenhagen University Hospital – and the University of Copenhagen have discovered why malaria parasites are able to hide from the immune defences of expectant mothers, allowing the parasite to attack the placenta. The discovery is an important part of the efforts researchers are making to understand this frequently fatal disease and to develop a vaccine. Staff member at CMP. Photo: Lars Hviid"We have found one likely explanation for the length of time it takes for the expectant mother's immune defences to discover the infection in the placenta," says Lea Barfod, MSc, who is working with Professor Lars Hviid at the Centre for Medical Parasitology, University of Copenhagen.
"The parasites are able to assume a camouflage that prevents their recognition by the immune system antibodies which would otherwise combat them. So although the immune system has all the weapons it needs to fight the infection of the placenta, these weapons are ineffectual simply because the enemy is hard to spot. Ironically the camouflage also consists of antibodies, but of a type that does not help to fight infection."
The malaria parasite at war with the immune system
One human being in twelve is infected with malaria. That means 500 million people are carrying the tiny parasite, and it kills a million of them a year. The disease costs so many lives because the parasite constantly outmanoeuvres the human immune system. It starts by hiding in the red blood cells. The immune system does not bother with these as the spleen usually filters defective blood cells.
To avoid this filter, the parasite ejects a protein hook which attaches to the inner wall of the blood vessel, and even if the immune system antibodies destroy one such hook, the parasite has more than sixty in its arsenal. One of them has evolved specially to attach to the placenta. While the war is being waged the parasite propagates and infects more and more red blood cells, which are normally used for transporting nutrients and oxygen around the body.

Fighting from house to house
"In an advanced version of hide-and-seek the parasites keep looking for new ways of preventing the antibodies from recognising them. It is a kind of urban guerrilla war in which the fighting is conducted from house to house," says Lars Hviid.
"One example is the ability of the parasites to hide in the placenta. The first time an African woman conceives her placenta provides a new opportunity for the parasite to hide: a new house, so to speak, and in a way that prevents discovery by the immune system. It takes time for the immune defences to react to the new threat, and meanwhile the camouflaged parasite harms the woman and her unborn child."
The researchers are now going to study whether the malaria parasite also uses its camouflage at other stages of an infection.
"Perhaps it is not only the parasites in the placenta that are capable of hiding like this," Lars Hviid says.
"It takes the body a surprisingly long time to develop protection from Malaria, and perhaps the trick we have just discovered is part of the explanation. It is important for us to find out if this is the case in order to help us to understand malaria in general, but also to help us in our efforts to develop a vaccination. We have plenty of work to be going on with," Lars Hviid concludes.

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Lea Barfod and Lars Hviid's discovery has just been published in the Proceedings of the National Academy of Sciences of the United States of America.

Contact: Professor Lars Hviid : lhviid@sund.ku.dk 452-274-7426 University of Copenhagen

MALARIA: Placental Malaria

Placental Malaria-Associated Suppression of Parasite-Specific Immune Response in Neonates Has No Major Impact on Systemic CD4 T Cell Homeostasis


Infection and Immunity, July 2011,p. 2801-2809, Vol. 79, No. 7: 019-9567/11/$12.00+0 doi:10.1128/IAI.00203-11
Valérie Soulard,1,2,* Martin Amadoudji Zin,3 Catherine Fitting,4 Samad Ibitokou,3 Mayke Oesterholt,5 Adrian J. F. Luty,5 René-Xavier Perrin,6Achille Massougbodji,3 Philippe Deloron,1,2,* Antonio Bandeira,7, and Nadine Fievet1,2
1Institut de Recherche pour le Développement UMR216 Santé de la Mère et l'Enfant en Milieu Tropical 2Université Paris Descartes, Faculté de Pharmacie, 4 Avenue de l'Observatoire, 75006 Paris, France 3Parasitology and Mycology Education and Research Unit, Science and Health Faculty, BP 188 Cotonou, Benin 4Cytokines and Inflammation, Department of Infection and Epidemiology, Institut Pasteur, Paris, France 5Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands 6Science and Health Faculty, BP 188 Cotonou, Benin 7Lymphocyte Development Unit, Department of Immunology, Institut Pasteur, Paris, France

In areas where Plasmodium falciparum is endemic, pregnancy is associated with accumulation of infected red blood cells (RBCs) in the placenta, a condition referred to as placental malaria (PM). Infants born to PM-positive mothers are at an increased risk ofmalaria, which is putatively related to the transplacental passage of parasite-derived antigens, with consequent tolerization of the fetal immune system. Here we addressed the impact of PM on the regulation of neonatal T cell responses. We found that the frequency of regulatory CD25+ CD127–/low Foxp3+ CD4+ T cells was significantly decreased in neonates born to mothers with high levels of P. falciparum-induced placental inflammation, consisting mainly of primigravid mothers. However, at the individual level, the ratio between regulatory and effector (CD25+CD127+ Foxp3–) CD4+ T cells was unaffected by PM. In addition, parasite-induced CD4+ T cell activation and production of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-10 were strongly reduced in neonates born to PM-positive mothers. Thus, our results show that active PM at delivery is associated with a marked suppression of P. falciparum-specific cellular neonatal immune responses, affecting secretion of both pro- and anti-inflammatory cytokines. Additionally, our results suggest that, as in adults, effector and regulatory CD4+ T cell populations are tightly coregulated in all neonates, irrespective of the maternal infection status.

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* Corresponding author. Mailing address for Philippe Deloron: IRD UMR 216 Santé de la Mère et l'Enfant en Milieu Tropical, Université Paris Descartes, 4 Av. de l'Observatoire, 75006 Paris, France. Phone: 33 1 53 73 96 22. Fax: 33 1 53 73 96 17. E-mail: philippe.deloron@ird.fr. Present address for Valérie Soulard: Inserm U986, Hôpital Saint- Vincent de Paul, 82 Av. Denfert-Rochereau, 75014 Paris, France. Phone: 33 1 43 21 72 98. Fax: 33 1 40 48 83 52. E-mail:valerie_soulard@yahoo.fr.