The Russian roulette of severe malaria

In less than two weeks my good friend Federica is going to hop on a plane to Senegal where she’ll spend 6 months studying primates in the wild. During this time she’ll have to venture through the jungle, live among the animals, examine their behaviour, produce some good science and, of course, avoid contracting any horrific tropical disease.

In order to do all this, she spent the past few weeks flooding her body with more vaccines than you could imagine and learning about all the possible deaths she could face (including slipping on the mud, falling in the river Gambia and being devoured by crocodiles). As a consequence of this, 90% of our conversations have been revolving around deadly African diseases such as yellow fever, meningitis, influenza and of course, every traveler’s top fear, malaria.

We were just having one of our lovely chats about gruesome illnesses when she told me:

“There is a good chance I will get malaria in Senegal, because there is no vaccine against it and the only preventative treatment available doesn’t really offer complete protection “. She also added: “Let’s just hope I get a mild form of it, because the closest hospital will be hours away. It will all depend on how my body reacts to it”.

Does it really? I knew malaria was caused by a parasite of the type Plasmodium and I knew that there are five different species of Plasmodium that can infect humans. However, as I later found out, 75% of malaria infections are caused by only one of these parasites, the Plasmodium Falciparum. So, how come that if most people are infected by the same parasite, some only experience very mild symptoms and require almost no medical attention, whereas some other progress to experience an extremely severe and even lethal disease?

This question didn’t leave me until, just a couple of weeks later, I stumbled across an interesting review about the molecular basis of severe malaria, by Deitsch and Chitnis. The review addresses exactly the question I had in mind.

Anopheles Albimanum mosquito, a typical vector for malaria (photo by James Gathany).

It all starts with a mosquito. The parasite P. Falciparum lives in the saliva of infected mosquitos so when the females of this apparently innocuous little insect feed on human blood, the parasite is able to migrate to the human body. After a couple of weeks of incubation in the liver, P. Falciparum spreads to the blood stream and hides inside our red blood cells. From its hiding place, it starts to produce a protein that sticks out of the blood cell’s membrane, called Pasmodium falciparum eythrocyte membrane protein 1 (and because I don’t want you to run out of breath every time you read this, I’ll just refer to it as PfEMP1 from now on). The function of this protein is to bind to the walls of veins and arteries, basically anchoring the whole cell like a boat and preventing it from flowing freely along the circulation. This allows the parasite to grow and multiply, until it eventually bursts out of the host cell and starts infecting new ones. During this stage of the illness the patient starts to experience all the rather unpleasant symptoms of malaria, including fever, vomiting, anaemia, organ damage and in the most severe cases these are followed by convulsions and coma.

However, our bodies are very good at recognising the foreign protein PfEMP1 and making antibodies against it to destroy all the infected red blood cells. So to bypass our immune system, the malaria parasite has developed many copies of a gene called var. Each var gene is similar but slightly different to the other ones and it encodes for a slightly different version of PfEMP1. By randomly switching from one copy of var to another, the sneaky parasite can create many different types of PfEMP1 until if finds one that isn’t recognised by our immune system. What’s more, each version of the protein PfEMP1 has varying ability to stick to the walls of blood vessels. This means that the severity of the disease depends on which copy of var is activated, explaining why some individuals exhibit mild symptoms whereas some others develop life-threatening malaria. In other words, we’re in front of a parasitic Russian roulette, where it’s pretty much down to luck which copies of the var gene get switched on in the invading parasite.

Understanding this mechanism means, in theory, that we could isolate the forms of PfEMP1 that are associated with severe disease

P. Falciparum and red blood cells (courtesy of Dr. Mae Melvin)

(the really sticky ones!) and develop vaccines that target them specifically. Unfortunately, this isn’t an easy task because of the great variability present in the var gene family. Each parasite can contain more than 60 different copies of var and these change significantly from region to region. However, a preliminary analysis has shown that var genes can be subdivided into three main groups which, for once, have been given really simple names: A, B and C. Of the three families it looks like group A is more often involved with the severe forms of the disease.

One of these, possibly the deadliest one, is cerebral malaria, where the infected red blood cells cross the blood brain barrier (which is supposed to protect the brain from pathogens) and can cause neurological damage, coma and death. Group A var genes are the only ones that produce versions of PfEMP1 able to bind to human brain cells. Luckily for us, when it comes to these aggressive versions of the protein, there seems to be a fairly limited diversity. Almost all forms of PfEMP1 that cause the most damage contain two protein domains (imagine them as small sections of the bigger protein) called DC8 and DC13. Several studies have confirmed that in most cases, group A var genes produce proteins that consistently include DC8 and DC13 segments. This discovery gives us a little more hope that one day we’ll be able to make a vaccine able to target these two portions of the protein, thus protecting people from at least the most dangerous forms of malaria, including cerebral malaria.

Even if our new and deeper understanding of malaria takes us one step closer to an effective malaria vaccine, I’m afraid that for now my friend will just have to take anti-malaria prophylaxis, cover her body in mosquito repellent and hide behind anti-mosquito nets.

Reference: http://www.pnas.org/content/109/26/10130.long

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