Mosquitoes are the world’s deadliest animal. More than 1 million deaths per year are attributed to mosquito-borne diseases, including malaria, yellow fever, dengue fever, Zika and chikungunya fever.
How mosquitoes seek out and feed on their hosts are important factors in how a virus circulates in nature. Mosquitoes spread disease by acting as carriers of viruses and other pathogens: a mosquito that bites a person infected with a virus can acquire the virus and pass it on to the next person it bites.
For immunologists and infectious disease researchers like me, a better understanding of a virus’s interaction with a host may provide new strategies for preventing and treating mosquito-borne diseases. In our recently published study, my colleagues and I found that some viruses can alter a person’s body odor to be more attractive to mosquitoes, leading to more bites that allow a virus to spread.
Viruses change host odors to attract mosquitoes
Mosquitoes locate a potential host through various sensory cues, such as your body temperature and the carbon dioxide emitted by your breath. Smells also play a role. Previous lab research has shown that mice infected with malaria have changes in their scents that make them more attractive to mosquitoes. With this in mind, my colleagues and I wondered if other mosquito-borne viruses, such as dengue and zika, could also alter a person’s smell to make them more attractive to mosquitoes, and if there was a way to prevent these changes. .
To investigate this, we placed mice infected with the dengue or Zika virus, uninfected mice and mosquitoes in one of three arms of a glass chamber. When we applied airflow through the mice chambers to direct their odors to the mosquitoes, we found that more mosquitoes chose to fly to the infected mice over the uninfected mice.
We excluded carbon dioxide as the reason why the mosquitoes were attracted to the infected mice, because while Zika-infected mice emitted less carbon dioxide than uninfected mice, dengue-infected mice did not change emission levels. Similarly, we excluded body temperature as a potential attractive factor when mosquitoes failed to distinguish between mice with elevated or normal body temperature.
Next, we assessed the role of body odors in the increased attraction of mosquitoes to infected mice. After placing a filter in the glass chambers to prevent mouse odors from reaching the mosquitoes, we found that the number of mosquitoes flying to infected and uninfected mice was similar. This suggests that there was something about the smells of the infected mice that drew the mosquitoes to them.
To identify the odor, we isolated 20 different gaseous chemical compounds from the odor emitted by the infected mice. Of these, we found three that stimulate a significant response in mosquito antennae. When we applied these three compounds to the skin of healthy mice and the hands of human volunteers, only one, acetophenone, attracted more mosquitoes than the control. We found that infected mice produced 10 times more acetophenone than uninfected mice.
Similarly, we found that the odors collected from the armpits of dengue fever patients contained more acetophenone than those of healthy people. When we applied the smell of dengue patients on the one hand of a volunteer and on the other hand the smell of a healthy person, mosquitoes were consistently more attracted to the hand with the smell of dengue.
These findings imply that the dengue and Zika viruses are able to increase the amount of acetophenone their hosts produce and emit, making them even more attractive to mosquitoes. When uninfected mosquitoes bite these attractive hosts, they can bite other people and even spread the virus further.
How do viruses increase acetophenone production?
Next, we wanted to find out how viruses increased the amount of mosquito-attracting acetophenone their hosts produce. Acetophenone is not only a chemical often used as a fragrance in perfumes, but is also a metabolic by-product commonly produced by certain bacteria that live on the skin and gut of both humans and mice. So we wondered if it had something to do with changes in the type of bacteria on the skin.
To test this idea, we removed the skin or gut bacteria from infected mice before exposing them to mosquitoes. While mosquitoes were still more attracted to infected mice with depleted gut bacteria compared to uninfected mice, they were significantly less attracted to infected mice with depleted skin bacteria. These results suggest that skin microbes are an essential source of acetophenone.
When we compared the composition of skin bacteria from infected and uninfected mice, we identified that a common type of rod-shaped bacteria, Bacillus, was a major producer of acetophenone and had significantly higher numbers on infected mice. This meant that the dengue and Zika viruses could alter their host’s odor by altering the skin’s microbiome.
Reduce mosquito-attracting odors
Finally, we wondered if there was a way to prevent this change in scents.
We found a possible option when we noticed that infected mice had reduced levels of an important microbe-fighting molecule produced by skin cells called RELMα. This suggested that the dengue and Zika viruses suppressed the production of this molecule, making the mice more vulnerable to infection.
Vitamin A and its related chemical compounds are known to strongly stimulate the production of RELMα. So, over the course of a few days, we gave a vitamin A derivative to infected mice and measured the amount of RELMα and Bacillus bacteria on their skin, and then exposed them to mosquitoes.
We found that infected mice treated with the vitamin A derivative were able to return their RELMα levels to those of uninfected mice, as well as increase the amount of Bacillus bacteria on their skin. Mosquitoes were also no more attracted to these treated, infected mice than uninfected mice.
Our next step is to replicate these results in humans and ultimately apply what we learn to patients. Vitamin A deficiency is common in developing countries. This is especially the case in sub-Saharan Africa and Southeast Asia, where mosquito-borne viral diseases are common. Our next steps are to investigate whether dietary vitamin A or its derivatives can reduce the attraction of mosquitoes to humans infected with Zika and dengue, and then reduce mosquito-borne disease in the long term.