Anopheles stephensi. Credit: CDC
Anopheles stephensi. Credit: CDC

Mosquitoes temper severity of malaria

In labs around the world, scientists study malaria by injecting rodents with Plasmodium—the parasites that cause the disease. These experiments are necessary but also artificial. In the wild, the needle that spreads malaria isn’t a hypodermic syringe, but a mosquito’s snout.

Both delivery routes end in infection, but they have very different effects. Philip Spence from the National Institute for Medical Research in London has found that malarial parasites cause less severe disease if they have spent time in a mosquito—that is, they become less virulent. Something in them changes so that when they move into a mammal, they trigger a stronger immune response, grow less well and cause milder symptoms.

A word of caution: This doesn’t mean that mosquitoes are protecting us from malaria. They’re not suddenly our allies. Instead, Spence’s study shows that they can temper the lethality of the disease that they spread. They’re not just a vector but a regulator.

It was in 1897 when Nobel prize-winner Ronald Ross found Plasmodium in the stomach of a mosquitoRonald Ross found Plasmodium in the stomach of a mosquitoRonald Ross found Plasmodium in the stomach of a mosquito that had bitten a malaria patient, and went on to show the parasite’s full life cycle. Now, 118 years later, “Spence has come full circle by uncovering a new way in which mosquitoes play a central role in malaria—not just by transmitting the disease but by modifying its severity too,” says Sarah Reece from Edinburgh University.

“I don’t remember being as excited about a basic malaria paper for a long time,” says Andrew Read from Pennsylvania State University, who studies the evolution of infectious diseases.

The study

When a malarial mosquito bites a human, Plasmodium travels down its snout into the bloodstream of its new host. Its first stop is the liver, where it reproduces before re-entering the blood and infecting red blood cells. Since the blood-stage is when the parasite causes disease, scientists often bypass the rest of the complicated life-cycle. They just transfer parasites from one animal’s blood to another’s. If you do this repeatedly—a technique called serial blood passage—the parasite seems to become more virulent, although no one knew why.

Jean Langhorne, who led the new research, was originally motivated by criticisms that these mouse experiments weren’t relevant enough for human diseases. “We wanted to make our mouse model as relevant as possible, so we wanted to transmit the parasite as naturally as possible,” she says.

Spence, a postdoc in her lab, worked with Plasmodium chabaudi—a species that causes malaria in rodents but produces similar symptoms to human malaria. When injected directly into a mouse’s blood, P.chabaudi grew rapidly and caused severe chills, weight loss, fatigue and liver damage. But when transmitted by a mosquito, it grew slowly and the mice barely suffered. They became anaemic, but not much else.

The same thing happens to the parasites that cause sleeping sickness after passing through their  tsetse fly vectors. “There was a feeling that this happens in malaria too but this is the first strong evidence for that,” says Read.

The mosquito-borne parasites trigger a very different immune reaction from the mice than those that are injected directly. The rodents marshal a bigger squadron of white blood cells to recognise the invaders and attack them with antibodies. At the same time, these cells produce fewer of the inflammatory molecules that are linked to severe disease.

But it’s not just about the host. Spence found that a spell in a mosquito changes the activity of around 10 percent of the parasite’s genes. These include the majority of the pir genes, which produce proteins that are recognised by the host’s immune system. The upshot is that the mice are better able to control their parasites if delivered by mosquito rather than syringe… but largely due to changes in the parasites themselves.

What does it mean?

Read says that the study reveals two sides to Plasmodium. The parasites have genes that trigger a strong immune response, which leads to mild, long-lasting infections and less collateral damage for their hosts. But they must also have genes that trigger a stronger short-term infection—that’s what you see if you inject them directly into the blood.

“Within its genome, the parasite has the capacity to produce two very different infection profiles,” Read says. Short, strong infections are a good strategy in an epidemic, when hosts are plentiful. But in long dry seasons, when there might not be any mosquitoes for months, “natural selection will produce infections that grumble on for a long time without making the host very sick. There won’t be just one type of malaria.”

But Margaret Mackinnon, who studies malaria at the KEMRI-Wellcome Research Programme in Kenya, cautions against thinking that the “parasite uses the vector to modify its virulence in order to stop itself from killing the host”. To her, it’s more that the  mosquito puts a natural brake on the parasite. Serial blood passages remove that brake and things go hay-wire. “But don’t worry, because this can never happen in nature,” says Mackinnon.

Indeed, some scientists say that the mosquito results only stand out because they use parasites that have already gone through several serial blood passages. “Blood passage is totally abnormal,” says William Collins from the Center of Disease Control. He praises the paper but disagrees that a stay in a mosquito reduces the parasites’ virulence. “Rather, mosquito transmission restores it to near that of the original level,” he says.

Sure, blood passage artificially inflates the parasite’s powers and in the wild, mosquitoes might reduce virulence to a much lesser extent. But “if the effects are smaller in a natural situation, it doesn’t mean that they aren’t important,” says Mackinnon. “Natural selection operates on small as well as large differences.”

Regardless of the interpretation, it’s clear that the study raises more questions than it answers. “There’s no question that it’s a very cool paper, but it feels like it’s a start of something,” says Read. For example, we only know that the parasite activates genes that affect the host’s immune system. But when? In the mosquito? In the liver? In the blood? And Reece wants to know if these genes interact with the mosquito’s own immune system, rather than just the mammal’s.

And, perhaps most importantly, how does the mosquito modify the parasite? Mackinnon puts forward three possibilities. It could be that a small (and genetically narrow) force of parasites makes it out of the mosquito, and they’re more easily handled by the immune system. Alternatively, virulent mutants might get weeded out during the infection because they’re harder to transmit. Or maybe the mosquitoes could trigger “epigenetic” changes that alter how the parasite’s genes are used without changing the sequences of the underlying DNA. Langhorne strongly suspects that the epigenetic explanation is right, and she’s planning to test it.

Reference: Spence, Jarra, Levy, Reid, Chappell, Brugat, Sanders, Berriman & Langhorne. 2013. Vector transmission regulates immune control of Plasmodium virulence. Nature

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