Flaviviruses, such as dengue and Zika, rely on mosquitoes for transmission. In addition, host-seeking activity of the mosquitoes is essential for viral transmission. Now, researchers have uncovered that the viruses have a mechanism to put the odds in their favor.

The findings suggest that the viruses make humans and mice that they have infected more attractive to mosquitoes. How do they do it? The viruses manipulate the hosts’ skin microbiota to produce a scent that attracts mosquitoes by increasing acetophenone-producing bacteria. Because acetophenone is a mosquito attractant, this makes the host more attractive to other mosquitoes, and facilitates viral transmission.

This research is published in Cell, in the article, “A volatile from the skin microbiota of flavivirus-infected hosts promotes mosquito attractiveness.

Group photo of investigators in front of the Medical Building, Tsinghua University. [Xi Yu]
“Mosquitoes rely on their sense of smell to detect hosts and guide fundamental behaviors of survival,” said Gong Cheng, PhD, professor at the school of medicine at Tsinghua University. “At the beginning of this study, we found that the mosquitoes preferred to seek and feed on dengue- and Zika-infected mice.”

To investigate why mosquitoes preferred infected hosts, the team performed a chemical analysis on odor samples from infected mice and humans. The group identified the attractant 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 flavivirus [like dengue and Zika] can utilize the increased release of acetophenone to help itself achieve its lifecycles more effectively by making their hosts more attractive to mosquito vectors,” said Cheng.

The team investigated how dengue and Zika viruses increase the level of acetophenone. They describe it as “a sophisticated interplay between hosts’ skin microbiota, flaviviruses, and mosquitoes.”

Investigators assessed mosquito behavioral response by a two-port olfactometer assay. Left to right: Hong Zhang, Yibin Zhu, Gong Cheng. [Xuan Guo]
When a flavivirus invades a host, the virus can alter the expression of an essential antimicrobial protein on host skin that regulates the composition of the skin microbiome—RELMα. Flavivirus infection, the authors write, suppressed the expression of RELMα, leading to the expansion of acetophenone-producing commensal bacteria and, consequently, a high acetophenone level.

“Intriguingly, both dengue and Zika viruses promoted the proliferation of acetophenone-producing skin bacteria by suppressing the RELMα expression,” Cheng said. As a result, some bacteria over-replicate and produce more acetophenone.

Given that RELMα can be specifically induced by a vitamin A derivative, the authors found that dietary administration of isotretinoin to flavivirus-infected animals interrupted the flavivirus life cycle by reducing mosquito host-seeking activity. The 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,” Cheng said. This may provide a strategy of arboviral control.

In the future, Cheng and his team are setting out to apply their findings in the real world. “We plan to dietarily administer isotretinoin in dengue patients to reduce acetophenone-mediated mosquito activity,” said Cheng.

They are attacking the issue from the mosquito side as well. “We plan to identify specific olfactory receptors for acetophenone in mosquitoes and remove the genes from the mosquito population by a gene drive technology,” Cheng explained. Without the receptors, mosquitoes will no longer be able to smell the acetophenone that they love so much, which will possibly mitigate the spread of dengue and other flaviviruses.