New research demonstrates that mosquito-transmitted flaviviruses such as Zika and dengue can manipulate skin microbiota of their hosts to produce a scent that attracts mosquitoes.
Dengue is spread by mosquitoes in tropical areas around the world, and occasionally in subtropical areas such as the southeastern US. It causes fever, rash, and painful aches, and sometimes hemorrhage and death. More than 50 million dengue cases occur every year.
Zika is another mosquito-spread viral disease in the family Flaviviridae. Although it is uncommon for Zika to cause serious disease in adults, a recent outbreak in South America caused serious birth defects in the unborn children of infected pregnant women.
Yellow fever, Japanese encephalitis, and West Nile are also members of this virus family.
These viruses require ongoing infections in animal hosts as well as mosquitoes in order to spread. If either of these are missing – if all the susceptible hosts clear the virus, or all the mosquitoes die – the virus disappears. For example, during the yellow fever outbreak in Philadelphia in 1793, the coming of the fall frosts killed the local mosquitoes, and the outbreak ended.
In tropical climates without killing frosts, there are always mosquitoes; the virus just needs one to bite an infected host animal in order to spread.
“Mosquitoes rely on their sense of smell to detect hosts and guide fundamental behaviors of survival,” said Dr. Gong Cheng, a researcher at the Tsinghua University-Peking University Joint Center for Life Sciences and the Institute of Infectious Diseases at the Shenzhen Bay Laboratory.
“At the beginning of this study, we found that mosquitoes preferred to seek and feed on dengue- and Zika-infected mice.”
To investigate why mosquitoes preferred infected hosts, Dr. Cheng and colleagues performed a chemical analysis on odor samples from infected mice and humans.
They identified the culprit that makes them smell more delicious as acetophenone, which was present at an abnormally high level in infected individuals.
This compound can also be found in many fruits and some cheeses.
“We found that flaviviruses can utilize the increased release of acetophenone to help itself achieve its lifecycles more effectively by making their hosts more attractive to mosquito vectors,” Dr. Cheng said.
The researchers then investigated exactly how dengue and Zika viruses increase the level of acetophenone.
When a flavivirus invades a host, the virus enters a tug-of-war with the cells in the host’s body to control the level of a key protein that regulates the composition of the skin microbiome – RELMα.
If the cells are winning, RELMα keeps the acetophenone-producing bacteria in check.
“Intriguingly, both dengue and Zika viruses promoted the proliferation of acetophenone-producing skin bacteria by suppressing the RELMα expression,” Dr. Cheng said.
As a result, some bacteria over-replicate and produce more acetophenone.
With a clearer understanding of how flavivirus affects the skin microbiome, the authors set out to find a way to help the cells to win the tug-of-war.
After examining existing RELMα literature, they decided to test whether isotretinoin – a vitamin A derivative commonly used as acne medicine – may suppress the production of acetophenone.
The experiment was simple: feed the mice with isotretinoin and put them in a cage with mosquitoes.
The results were encouraging. The team found that mosquitoes did not feed on isotretinoin-treated infected mice any more than those feeding on uninfected animals.
“Dietary administration of isotretinoin, in flavivirus-infected animals, reduced acetophenone volatilization by reshaping resident commensal bacteria on the host skin,” Dr. Cheng said.
The results appear in the journal Cell.
Hong Zhang et al. A volatile from the skin microbiota of flavivirus-infected hosts promotes mosquito attractiveness. Cell, published online June 30, 2022; doi: 10.1016 / j.cell.2022.05.016