Why Do Mosquitoes Bite Humans?

The mosquito Aedes aegypti, which preys on humans in tropical and subtropical regions, is the main vector for dengue and yellow fever. In a recent Nature paper, a team of researchers have uncovered a gene that enables these mosquitoes to target humans.

To track down the gene, the researchers took advantage of the fact that not all Ae. aegypti prefer to bite humans. The species originated in the forests of sub-Saharan Africa, where it fed on non-human animals. In East Africa, the black-coloured subspecies Ae. aegypti formosus avoids coming into homes, preferring to stay in the forests, where it lays its eggs in rock pools and preys on non-human animals. The brown-coloured Ae. aegypti aegypti, on the other hand, readily comes into homes and bites humans, and has adapted to starvation in its larval stage, since the eggs are laid in water found in indoor containers, which is often nutrient-poor. By comparing the behaviour and genetics of the two subspecies, forest and domestic, the researchers hoped to figure out why one prefers humans.

They started by testing how the two subspecies responded to nylon sleeves which had been worn by humans or guinea-pigs. The experiment confirmed the difference in taste; the domestic subspecies showed a preference for the human-scented sleeve, while the forest subspecies was indifferent. Mosquitoes smell with their antennae, so the team reasoned that there might be an important difference in gene expression in the antennae. They could use RNA sequencing to get a snapshot of gene expression in the antennae, but comparing the two subspecies generated a list of nearly 1,000 genes, including many involved in other process — after all, the forest and domestic forms differ in more than just their prey preference. To tighten their search, the team crossed the two subspecies to make a hybrid pool and then picked out the hybrids that had a strong preference for humans or guinea-pigs. Hybridizing the subspecies smoothed out the genetic differences between them, so the human and guinea-pig preferring hybrids were separated by differential expression of just 46 genes. The two lists — 1,000 genes and 46 genes — had an overlap of only 14 genes, two of which encoded odorant receptors. The team focused their efforts on one of the two, called OR4.

The next step was to figure out if and how OR4 responds to human odors. By cloning the gene into a Drosophila neuron, the researchers could test its response to different chemical cues in a controlled manner. OR4 didn't respond to the different components that make up a guinea-pig's smell, but it did respond when exposed to sulcatone, a chemical which is emitted at higher levels by humans than other animals. The malaria mosquito, Anopheles gambiae, also has several odorant receptor genes that respond strongly to sulcatone, but none of them is closely related to the Ae. aegypti OR4. The two mosquito species, separated by 300 million years of evolution, have independently evolved a taste for this human marker.

The team identified several alleles of OR4 in Ae. aegypti populations. A preference for biting humans depends on having an allele that is strongly expressed and is sensitive to sulcatone. However, it seems that sulcatone alone may not be enough — guinea-pig odor with added sulcatone was no more attractive to human-biting mosquitos than guinea-pig odor alone. In addition, despite being an attractant at low levels, sulcatone acts as a mosquito repellent at sufficiently high concentrations. Sulcatone and OR4 are clearly just part of a complex ecological and evolutionary interaction between mosquitos and their meals.

Ref
McBride, Carolyn S. et al. Evolution of mosquito preference for humans linked to an odorant receptor. Nature 515(7526):222. (2014) doi:10.1038/nature13964

Image credits
The Aedes aegypti image is by James Gathany and is in the public domain as a work of the CDC.