Malaria-induced changes in host odors enhance mosquito attraction

Vector-borne pathogens may alter traits of their primary hosts in ways that influence the frequency and nature of interactions between hosts and vectors. Previous work has reported enhanced mosquito attraction to host organisms infected with malaria parasites but did not address the mechanisms underlying such effects. Here we document malaria-induced changes in the odor profiles of infected mice (relative to healthy individuals) over the course of infection, as well as effects on the attractiveness of infected hosts to mosquito vectors. We observed enhanced mosquito attraction to infected mice during a key period after the subsidence of acute malaria symptoms, but during which mice remained highly infectious. This attraction corresponded to an overall elevation in the volatile emissions of infected mice observed during this period. Furthermore, data analyses—using discriminant analysis of principal components and random forest approaches—revealed clear differences in the composition of the volatile blends of infected and healthy individuals. Experimental manipulation of individual compounds that exhibited altered emission levels during the period when differential vector attraction was observed also elicited enhanced mosquito attraction, indicating that compounds being influenced by malaria infection status also mediate vector host-seeking behavior. These findings provide important insights into the cues that mediate vector attraction to hosts infected with transmissible stages of malaria parasites, as well as documenting characteristic changes in the odors of infected individuals that may have potential value as diagnostic biomarkers of infection.Parasite manipulation of hosts is a widespread phenomenon with broad significance for ecology and human health (1–5). Increased attention has recently focused on manipulation by vector-borne parasites (2, 6, 7), which may enhance their own transmission via direct effects on vector behavior (6–10) or by altering traits of their primary hosts in ways that influence vector attraction and dispersal, as well as the likelihood of pathogen acquisition by vectors during interactions with the primary host (6, 7, 10–12). In the case of pathogens vectored by insects, host odors seem particularly likely targets for manipulation, as olfactory cues play a key role in host location and discrimination by both plant- and animal-feeding insects. And a number of recent studies have documented pathogen-induced effects on volatile mediated host-vector interactions (11–16). In addition to their ecological significance, pathogen-induced changes in host-derived olfactory cues have potential applied implications for efforts to disrupt vector transmission (e.g., via the development of chemical lures or repellents), as well as for disease diagnosis. Indeed, given that a key challenge for the development of volatile-based diagnostics lies in recognizing the “signal” of disease presence against the background “noise” of genetic and environmental variation (17), it is plausible that volatile biomarkers will prove particularly valuable for detecting pathogens that actively manipulate host odors, although little work to date has explored this possibility.The current study explores potential manipulation of host odors by protozoan parasites in the genus Plasmodium responsible for causing malaria, which remains among the deadliest of human diseases and a significant hindrance to economic development in regions where it occurs (18, 19). A good deal of previous research has documented effects of the plasmodium parasites on the physiology and behavior of mosquito vectors (8, 10, 20–24). There is reason to suspect that manipulation of host odors by these parasites also influences vector behavior. For example, a provocative study found that Kenyan children harboring the transmissible (gametocyte) stage of the malaria parasite Plasmodium falciparum were more attractive to mosquitoes than uninfected children or those harboring the nontransmissible stage of the parasite (25). The cues responsible for this enhanced attraction were not identified, but parasite-induced changes in host odors seem the likeliest explanation, as the attraction occurred at a distance and was apparently not explained by variation in body heat or activity (as all of the children involved in the study were asymptomatic). A subsequent study documented preferential blood feeding by the mosquito Culex pipiens on canaries (Serinus canaria) infected with the avian malaria parasite Plasmodium relictum, but the cues mediating this preference were again not determined (26).As noted above, the identification of pathogen-induced changes in host odors that influence vector behavior has potential applied implications, and this is particularly true for malaria. Minimizing transmission by mosquito vectors is a key focus of efforts to control this devastating disease, but resistance evolution poses a continual challenge for strategies that entail suppressing vector populations (27–30). An improved understanding of the ecological mechanisms mediating vector transmission may inform the development of more effective and sustainable control strategies. Furthermore, the ability to effectively direct drug treatments and other interventions to asymptomatic carriers of infection is a key issue for controlling disease spread and likely essential for the long-range goal of malaria eradication (31). Thus, the presence of volatile biomarkers capable of distinguishing asymptomatic individuals bearing the transmissible stage of the disease—as suggested by the findings of the Kenyan field study discussed above—could potentially have great diagnostic value.With these issues in mind, we initiated laboratory studies using a mouse model and the rodent malaria parasite Plasmodium chabaudii to confirm and elucidate the role of parasite-induced volatile cues in mediating preferential vector attraction to infected individuals. Our specific goals were to assess the relative attractiveness of infected individuals to mosquito vectors (compared with healthy controls) over the course of infection and to document associated differences in the volatile profiles of healthy and infected individuals.