Mosquitoes adapt to different habitats and feed on a variety of animals. Anthropophilic female mosquitoes, such as
Aedes aegypti and
Anopheles gambiae, have a strong innate drive to detect their human hosts and acquire blood meals for their egg production [
1]. Their biting behavior is not only annoying but also transmits many life-threatening diseases.
Aedes aegypti has evolved to specialize in biting humans and is the vector of many mosquito-borne diseases, such as dengue virus (DENV), Zika virus (ZIKV), yellow fever virus (YFV), and chikungunya virus (CHIKV) [
2].
Anopheles gambiae, the malaria vector, has also developed a preference for humans, which makes it an effective vector for disease transmission. Many mosquito-borne infectious diseases pose an increasing global health threat, and consequently, there is an urgent need to control their transmission.
Mosquitoes use a combination of cues to find their vertebrate hosts. These cues include host body temperature, carbon dioxide, and odors, with host odor being critical for host detection. Human odors are a complex blend of volatile organic compounds (VOCs). Human sweat is odorless, and the host skin microbiota plays a critical role in the decomposition of human sweat and the generation of VOCs released by the host [
3]. The skin microbiota can break down carbohydrates, fatty acids, and peptides on the skin into VOCs that mosquitoes can differentiate [
4]. So, the composition of the skin microbiota affects the degree of attractiveness of human beings to mosquitoes [
5]. Among these VOCs, carboxylic acid, ammonia, amines, lactic acid, aldehydes, ketones, 1-octen-3-ol, and sulfides have been identified to elicit both electrophysiological and behavioral responses in
Ae. aegypti and
An. gambiae [
6–
8]. Host-released VOCs are sensed by olfactory receptors located on the antennae, maxillary palps, and proboscis of mosquitoes [
9]. Therefore, taking measures to remold host odor can reduce the frequency of mosquito bites on the host and reduce the transmission of mosquito-borne infectious diseases to some extent.
To explore the mystery of the rapid spread of mosquito-borne viruses, a study by Zhang
et al. [
10] explained why hosts infected with flaviviruses are more “attractive” to mosquitoes. In the study, two different behavioral assays (three-cage olfactometer and two-port olfactometer) were used to analyze the changes in attractiveness to mosquitoes of flavivirus-infected mice and humans. The results showed that DENV- and ZIKV-infected mice were more attractive to female
Aedes mosquitoes and demonstrated that the increase in attractiveness was due to the VOCs of the infected mice and not CO
2 or body temperature. Based on these observed results, the authors collected VOCs from uninfected, DENV-infected, and ZIKV-infected mice and compared the components using gas chromatography–mass spectrometry (GC–MS). Electroantennography assays were used to test the 20 potential odorants, and acetophenone was identified as the key attractant in the virus-infected mice. At the same time, the authors found that acetophenone was also increased in dengue patients and that the VOCs from dengue patients were more attractive to female mosquitoes than those from uninfected individuals. These findings suggest a “novel diagnosis” for dengue, such as an electronic “nose” or sensors that detect acetophenone released by dengue patients. Compared to a blood test, the new diagnostic method for dengue is much faster and easier.
Acetophenone is a common metabolic byproduct derived mainly from bacteria [
11]. The authors prepared uninfected and flavivirus-infected mice with or without commensal microbiota using specific antibiotic treatments. The results of the behavioral tests indicated that the commensal microbiota associated with mouse skin, rather than the gut, was the main source of attractants for mosquitoes. The sources of acetophenone released from flavivirus-infected mice in this study were identified from skin microbiota. Among them,
Bacillus flexus,
Bacillus megaterium,
Bacillus proteolyticus and
Bacillus wiedmannii were cultural and were shown to be involved in increased acetophenone production. To determine how flaviviruses increase the abundance of acetophenone-producing skin bacteria, the authors performed whole-transcriptome RNA sequencing (RNA-seq) to compare the abundance of transcripts in the skin of flavivirus-infected mice with that in the skin of uninfected animals. The results showed that
Retnla was the most significantly downregulated gene in the skin of flavivirus-infected mice.
Retnla is a gene encoding the protein resistin-like molecule-α (RELMα), an antimicrobial protein specifically expressed by epidermal keratinocytes and sebocytes [
12]. The RELMα antimicrobial protein targets and reduces the viability of
Bacillus spp., allowing
Bacillus spp. to proliferate and produce acetophenone on the skin of flavivirus-infected mice.
Mosquito-borne viruses cause hundreds of millions of infections worldwide each year. DENV causes an estimated 390 million infections, of which approximately 500 000 are severe cases requiring hospitalization and of which more than 20 000 cases result in death [
13]. Millions of infections were caused by ZIKV during its rapid and widespread transmission from 2015 to 2017 [
14]. Although mosquito-borne viruses have spread throughout much of the world and pose major public health concerns, there are no effective therapeutics against most mosquito-borne viruses, and vaccines have been developed for only a few species of flaviviruses, such as DENV and YFV. Blocking transmission has become an important measure for controlling mosquito-borne viruses, and the study by Zhang
et al. has developed and identified a promising countermeasure. Vitamin A derivatives have previously been found to be effective in inducing RELMα expression [
12]. The authors treated flavivirus-infected mice with oral administration of isotretinoin, a vitamin A derivative, and found that isotretinoin could decrease flavivirus transmission by reducing acetophenone-producing
Bacillus spp. through increased RELMα expression. The study opens new possibilities for interventions in mosquito-borne virus transmission by altering the composition of the host microbiome.
In summary, Zhang et al. found that flaviviruses promote the proliferation of acetophenone-producing skin bacteria, which enhances attraction to mosquitoes and promotes flavivirus transmission. The study not only revealed the mechanism by which the skin microbiota of the flavivirus-infected host attracts mosquitoes but also provided a solution to this phenomenon, namely, reshaping the composition of the infected host’s microbiome through the moderate intake of vitamin A derivatives. In the future, we are setting out to apply our findings in the real world. And we plan to dietarily administer vitamin A derivatives in dengue patients to reduce acetophenone-mediated mosquito activity. Also, we can attack the issue from the mosquito side. We plan to identify specific olfactory receptors for acetophenone in mosquitoes and remove the genes from the mosquito population by a gene drive technology. Without the specific receptors, mosquitoes will no longer be able to sense the acetophenone released with larger quantity from dengue patients. The promising findings by Zhang et al. provide guidance for the future prevention of mosquito-borne infectious diseases and new insights for effectively combating the spread of mosquito-borne viruses.
1 Compliance with ethical guidelines
Hong Zhang, Xi Yu, Yibin Zhu, and Gong Cheng declare that they have no conflicts of interest. This manuscript is a perspective article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.
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