How Viral Infections Attract Mosquitos that Transmit Those Viruses

A new study shows how certain viruses “call mosquitos home” to continue their life cycle.

As the nights get warmer here in Connecticut, I’m spending more and more time at dusk outside with my family. And alongside the ritual of roasting marshmallows for s’mores comes another ritual — complaining about who is getting bitten more by mosquitos.

Why is it that I am relatively spared from those pesky vectors of disease, while my wife and son are positively swarmed? I always joke that it’s because they are sweeter.

And it turns out that may not be far off the mark. A new paper in the journal Cell has shown not only that mosquitos are attracted to certain smells, but that certain mosquito-borne viruses change how we smell. The infection calls the mosquitos in.

It’s a crazy bit of evolution and a potential new avenue to decrease the spread of vector-borne diseases.

The idea that vector-borne diseases make you more attractive to the given vector is not entirely new. In fact, this phenomenon has been pretty clearly demonstrated in malaria. Controlled experiments have found that individuals infected with the malaria parasite are bitten more than control individuals.

But mosquitos don’t only harbor malaria. Flaviviruses, like Dengue and Zika virus — the latter becoming steadily more prevalent in the US — lead to tens-of-millions of infections a year. And, until now, no one has shown if they can change our attractiveness to mosquitos like malaria does.

But now researchers led by Gong Cheng in China have demonstrated, fairly conclusively, that these viruses do more than infect astrocytes, trophoblasts, and monocytes. They make us more appealing to mosquitos too. Cheng and colleagues also show us almost exactly how it works.

The experimental setup is pretty clever.

It looks like this — put a bunch of mosquitos in a chamber. On one side, you put a mouse infected with a flavivirus like Zika. On the other, an uninfected mouse.

The researchers showed that, instead of the 50/50 mosquito split you would ordinarily see, 70% of mosquitos head toward the Zika-infected mouse.

Of course, infection does a lot of things, including causing fevers. To prove that the mosquitos weren’t just being attracted to higher body temperatures, the researchers injected mice with lipopolysaccharide — a potent fever inducer. The mosquitos didn’t seem to care. They were equally attracted to control mice, and febrile mice, provided the latter were not actually infected with a flavivirus.

Mosquitos like carbon dioxide, we’re told, but it turns out that, as the mice get sick from Zika infection, they actually generate less carbon dioxide than uninfected mice — so that’s not what’s driving the blood-suckers.

Could it be that infected mice smell different?

To test this, the researchers put a smell filter between the mice and the mosquitos — something that would block all those odorant molecules. Now the mosquitos had no particular preference between infected and uninfected mice.

It was becoming clear that smell was the thing, so the researchers did what any self-respecting scientist with access to a mass spectrometer would do — they identified every volatile compound coming from infected and uninfected mice, ultimately identifying 11 compounds that were fairly dramatically upregulated in infection.

Which of those drive the mosquitos crazy? Well, they systematically exposed mosquitos to each of the 11 chemicals to see which ones made their antennas twitch most.

(I’m told this is a good signal that the smell is attractive to the mosquito). One stood out above the rest — acetophenone. It was about 10-times higher in infected mice compared to uninfected mice. And sure enough, if you paint some acetophenone on healthy mice — or human hands, the mosquitos love it.

Acetophenone is an aromatic ketone which apparently smells something like almond. Perfumers use it for its notes of cherry and honeysuckle as well — though you probably wouldn’t want to wear those particular perfumes in Dengue country.

Through some clever analysis of skin bacteria, the researchers were even able to determine how, exactly, flaviviruses promote this smell. Basically, they inhibit an antibacterial molecule called resistin-like molecule alpha. Without that substance on the skin, the bacteria flora starts to change, leading to the growth of bacteria that produce — you guessed it — acetophenone.

Now, of course, this is a mouse study primarily, but the researchers actually recruited patients infected with Dengue to confirm some of the findings. They showed, for example, that acetophenone levels were significantly higher in humans infected with dengue than controls. They also showed that mosquitos were more attracted to the odor of dengue-infected humans (this was an experiment that involved swabbing the armpits of Dengue-infected and healthy humans — the things we do for science).

Overall, this paper is a really impressive piece of work, highlighting the complex interplay of virus, primary, and secondary hosts. It is a dramatic example of the power of evolution as well. Flaviviruses like Zika and Dengue have no idea what a mosquito is, or that they require them for reproduction. But flaviviruses that make their hosts smell good to mosquitos will have a competitive advantage. Flaviviruses, by exploiting a chain of infection from human, to mosquito, to human, to mosquito — end up bringing humans and mosquitos closer together. Breaking that chain is key to controlling these epidemics.

Now, I wanted to talk about this study mostly because it is really cool — just a nice piece of science. The truth is, we already have a lot of tools to fight vector-borne illnesses ranging from the simple mosquito net, to genetically-engineered death mosquitos that can reproduce but their offspring don’t survive. Understanding how our smell changes how attractive mosquitos find us doesn’t mean we’ll be avoiding bug spray anytime soon. But that’s the thing about greater understanding. In retrospect, it can be easy to see where breakthroughs happen. In the moment, though, it is often unclear what new knowledge will lead to the world being changed. The best we can do is say — huh — this is pretty cool — and let the next group of scientists take the next step. But any step that brings us closer to an end of our age-old battle with mosquitos will be a welcome one.

A version of this commentary first appeared on Medscape.com.

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F. Perry Wilson, MD MSCE

F. Perry Wilson, MD MSCE

Medicine, science, statistics. Associate Professor of Medicine at Yale University. New book “How Medicine Works and When it Doesn’t” for pre-order now.