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Infection With Tropical Viruses Can Make You Smell Tastier to Mosquitoes

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Researchers have found that infection with some viruses like dengue or Zika – which spread through mosquito bites – can actually change the scent of their infected host, making them more attractive to hungry mosquitoes and increasing disease transmission.

The study, using data from both mice and humans, was published in the journal Cell.

Dengue and Zika viruses

Dengue virus (DENV) and Zika virus (ZIKV) are both members of the Flaviviridae family of single-stranded RNA viruses, found mainly in tropical and sub-tropical areas. Both DENV and ZIKV spread from person to person via the bites of infected mosquitoes, mainly the Asian tiger mosquito (Aedes albopictus) and the yellow fever mosquito (Aedes aegypti).

DENV infection results in dengue fever. There are an estimated 390 million infections per year, and this incidence is increasing. Approximately 80% of these infections are mild or asymptomatic; however, some people will experience a more severe, flu-like illness with fever, headaches, muscle pain and vomiting. A small number of these cases can progress to what is known as severe dengue or dengue hemorrhagic fever, a potentially fatal complication and a leading cause of hospitalization and death in some Asian and Latin American countries.

ZIKV on the other hand often has no or very minimal symptoms such as fever, rash, headache and red eyes, which persist for 2–7 days. Nonetheless, ZIKV infection can present serious problems during pregnancy. This was first reported during an outbreak in Brazil in 2015, when ZIKV infection during pregnancy was associated with infants being born with brain defects such as microcephaly – a condition in which the head and brain are much smaller than normal.

There are no effective treatments for either DENV or ZIKV and the emphasis of current research very much lies on preventing infection. However, in areas such as the tropics where mosquitoes thrive, this is easier said than done.

Previous research into malaria has shown that the disease-causing parasite Plasmodium falciparum can alter the scent of its host by manipulating the production of odorous molecules from the skin known as volatiles. These are detected by mosquitoes and trigger feeding behavior, making infected hosts more attractive to mosquitoes and increasing transmission. With this in mind, a team of researchers from institutes including the University of Connecticut, Tsinghua University in Beijing and the Institute of Infectious Diseases in Shenzhen hypothesized that DENV and ZIKV may manipulate their hosts’ scents in a similar way and planned a study to investigate whether they could inhibit this to prevent transmission.

Measuring mosquito responses to viral infection

The study used a series of tests known as olfactometer assays, which exposed the mosquitoes to different scents and allowed researchers to monitor their responses. A system of small chambers and tubes carried a flow of air in one direction, with experimenters directing airflow from chambers containing different groups of experimental mice – either infected or uninfected – into a chamber housing the mosquitoes. Investigators then monitored the behavior of the mosquitoes to see if they approached and indicated a preference for the scent of one group over another.

Firstly, the findings showed that mosquitoes preferentially entered the chambers where airflow came from either DENV- or ZIKV-infected mice compared to uninfected mice, and that this was the case for both A. aegypti and A. albopictus mosquito species. Additionally, the researchers found that samples of volatiles extracted from the skin of dengue patients were more attractive than samples from healthy volunteers.

To understand what compounds were provoking this response in the mosquitoes, the researchers collected and characterized the volatiles emitted from the mice using gas chromatography-mass spectrometry (GC-MS). They found that the abundance of 20 compounds were significantly changed in both DENV- and ZIKV-infected mice and that one of these compounds – acetophenone – was a strong activator of mosquito host-seeking behavior. Additionally, acetophenone production on the skin of infected mice was approximately 10 times higher than on uninfected mice.

Sequencing of RNA from skin cells revealed that expression of the anti-microbial molecule resistin-like molecule-α (RELMα) was significantly decreased during DENV and ZIKV infection. This was associated with an increased abundance of Bacillus bacteria on the skin, a major producer of acetophenone. This suggests that DENV and ZIKV promote the growth of acetophenone-producing bacteria by decreasing RELMα expression, thereby attracting and stimulating feeding behavior in mosquitoes.

We are very excited to identify acetophenone from host skin microbiota as the targeted volatile compound to manipulate the feeding motivation of mosquitoes,” said Professor Gong Cheng, professor at Tsinghua University School of Medicine and leader of the research unit in charge of the study, speaking to Technology Networks.

Taking acetophenone off the menu

Once they had identified acetophenone as the compound responsible for attracting the mosquitoes, researchers investigated whether they could target and reduce acetophenone production. Previous research has shown that vitamin A derivatives such as isotretinoin can increase RELMα production in skin cells to help resist infection. Therefore, researchers in the current study treated DENV- and ZIKV-infected mice with dietary isotretinoin, which significantly lowered the abundance of Bacillus on their skin and decreased their attractiveness to mosquitoes. This significantly reduced the number of virus-positive mosquitoes.

“Our study indicated that oral administration of isotretinoin might rescue the expression of RELMα in the skin of flavivirus-infected animals, thereby suppressing the growth of acetophenone-producing bacteria to reduce the mosquitoes’ host-seeking motivation,” Cheng elaborates.

However, isotretinoin treatment can come with a number of serious side effects. These include impaired liver function, serious birth defects or miscarriage if used in early pregnancy and somewhat controversial associations with mood disorders such as depression.

“Although isotretinoin has been widely clinically used for curing acne or other bacterial skin infections, oral administration of isotretinoin may cause risk of neuropsychiatric symptoms in humans,” Cheng explains. “Now, we are in discussion with our collaborators in Malaysia to select a safe and suitable vitamin A derivative for the following clinical investigation.”

Next steps: the human microbiome and genetically modified mosquitoes

The researchers now seek to address some of the limitations of the original study. “We think the major limitation is that the results are primarily derived from a mouse model. Because mouse skin physiology is quite different from that of human skin, there may be differences in the commensal flora between mice and humans,” explains Cheng.

To investigate changes to the skin microbiome and acetophenone production in human subjects, Cheng and colleagues intend to recruit and treat dengue patients in endemic areas with isotretinoin or other vitamin A derivatives. Additionally, they plan to create a genetically modified line of mosquitoes in which they seek to remove the gene(s) that produce acetophenone receptors, effectively removing their ability to detect acetophenone from infected hosts and reducing virus transmission.

Overall, the researchers hope that increasing our understanding of infection with DENV and ZIKV and mosquito response will offer valuable insights into controlling the spread of these diseases.

Prof. Gong Cheng was speaking to Sarah Whelan, Science Writer for Technology Networks.

Reference: Zhang H, Zhu Y, Liu Z, et al. A volatile from the skin microbiota of flavivirus-infected hosts promotes mosquito attractiveness. Cell. 2022:S0092-8674(22)00641-9. doi: 10.1016/j.cell.2022.05.016