Plasmodium-associated changes in human odor attract mosquitoes

Abstract

Malaria parasites (Plasmodium) can change the attractiveness of their vertebrate hosts to Anopheles vectors, leading to a greater number of vector–host contacts and increased transmission. Indeed, naturally Plasmodium-infected children have been shown to attract more mosquitoes than parasite-free children. Here, we demonstrate Plasmodium-induced increases in the attractiveness of skin odor in Kenyan children and reveal quantitative differences in the production of specific odor components in infected vs. parasite-free individuals. We found the aldehydes heptanal, octanal, and nonanal to be produced in greater amounts by infected individuals and detected by mosquito antennae. In behavioral experiments, we demonstrated that these, and other, Plasmodium-induced aldehydes enhanced the attractiveness of a synthetic odor blend mimicking “healthy” human odor. Heptanal alone increased the attractiveness of “parasite-free” natural human odor. Should the increased production of these aldehydes by Plasmodium-infected humans lead to increased mosquito biting in a natural setting, this would likely affect the transmission of malaria.Parasite transmission often constitutes a population bottleneck: Of the many parasites within one host, only a few are successfully transmitted to the next (1). Hence, parasites often evolve to exert influence over the transmission events. The malaria parasite Plasmodium would benefit from increasing its infected vertebrate host’s attractiveness to susceptible Anopheles mosquito vectors, if this resulted in increased contact rates between the two hosts. Such changes in attractiveness have been demonstrated in both animal (2⇓⇓⇓–6) and human (7⇓–9) malaria systems, as well as in other vector-borne disease systems (10⇓⇓–13). While manipulation of the “attractiveness” phenotype by the parasite has been suggested (5⇓⇓⇓–9), it is difficult to disentangle this from some by-product of infection that fortuitously leads to increased host attractiveness and subsequently transmission. Body odor, comprising the volatile compounds emitted from the skin of vertebrates, is the most important cue used by Anopheles for host location (14). It has been shown that differences in the composition of skin odor are responsible for the variation in attractiveness to biting insects known to exist between people (15, 16), and these differences may be influenced by body weight and/or surface area, hormones, or genetic factors (17⇓–19). Human body odor can also be influenced by disease, including metabolic disorders, genetic disorders, and infections (20). A study of Plasmodium infection in mice found such changes in body odor to be associated with changes in attractiveness to mosquitoes (6), and another found compositional changes in skin odor during controlled human malaria infection (CHMI), with a variable effect on attractiveness (21). While increased attractiveness of Plasmodium-infected individuals has been demonstrated in a malaria-endemic setting (9), remarkably, no study has yet investigated the skin chemistry underlying this phenomenon. Given the crucial importance of body odor to mosquito host location, and the proposition that body odor can be altered during disease, here, we hypothesize that infection with Plasmodium parasites changes the odor of humans and that this influences attractiveness of humans to mosquitoes. To test this hypothesis, we first confirmed that asymptomatic children in Western Kenya were more attractive to mosquitoes when harboring Plasmodium parasites, before comparing skin odor composition between Plasmodium-infected and parasite-free children from the same population. Using analytical chemistry, and the antennal and behavioral responses of Anopheles mosquitoes, we identified and established the role of Plasmodium infection-associated compounds (IACs) in human body odor................