Malaria is the most important human parasitic disease.
It is caused y an intra-erythrocytic Apicomplexa protozoa of Plasmodiidae family and Plasmodium genus. This parasite is transmitted by the bite of an infected female mosquito of Anopheles genus during a blood meal .
However, the parasite transmission often constitutes a population bottleneck*  and a key challenge faced by many parasites including Plasmodium, is how to move between hosts to complete their life cycle.
Therefore, parasites often evolve to exert influence over transmission events and some parasites manipulate their hosts in elaborate ways.
Thus, Plasmodium would take an advantage to modify and increase 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 and human malaria systems –, as well as in other vector-borne disease systems –.
While manipulation of the “attractiveness” phenotype by the parasite has been suggested –, it is difficult to disentangle this from underlying products of infection that fortuitously leads to increased host attractiveness and subsequent transmission.
Body odour from the vertebrate skin releases a diversity of volatile compounds such as the aldehydes. These oxygenated compounds can be synthesized when reactive oxygen species attack lipid-dense membrane structures , caused by oxidative stress**, a phenomenon known to characterize the malaria infection .
By its composition, the body odour represents the most important cue used by hematophagous insects such as Anopheles mosquitoes to localize their hosts , .
Moreover, the differences in the composition of the skin odour are responsible for the variation in attractiveness to biting insects known to exist between people , , and they may be influenced by different biological factors (body weight and/or surface area) or by genetic factors ,  but also by disease and infections .
While studies revealed that modifications in the skin body odour were associated with changes in the mosquito attractiveness , , , remarkably, no study has yet investigated the skin chemistry underlying this phenomenon.
Recently, researchers from the London School of hygiene and tropical medicine collaborated with researchers from Wageningen University (Netherland), Cardiff University (UK), Zurich University (Switzerland) and the University of Nairobi (Kenya) to study this question making the hypothesis that the Plasmodium infection would modify the human body odour, therefore, it would influence the attractiveness of humans to mosquitoes.
Using analytical chemistry, and the antennal and behavioural responses of Anopheles mosquitoes, they identified and established the role of Plasmodium infection-associated compounds (IACs) in human body odour.
Their results are published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) .
In a first time, researchers examined whether the Plasmodium infection could modify the attractiveness of human hosts to mosquitoes. They collected 45 samplings of foot odours from Kenyan children at two different time points (T1 and T2).
Among these samplings, 33 were infected by Plasmodium and 12 were free-parasite.
T1 represented the sampling time point did within 24h following antimalarial treatment while T2 represented the sampling time point made 21 days after the administration of the treatment.
Thus, via olfaction experiments, researchers measured the behavioural response of Anopheles. gambiae to these odours and for the different sampling time points.
Globally, results showed that mosquitoes were more attracted to odours from infected patients than by odours from non-infected patients.
Moreover, mosquitoes were more attracted by odours from infected children, sampled during the infection, so at T1, than by odours from these same children at T2.
However, mosquitoes did not differentiate between T1 and T2 odour samples from parasite-free children, indicating that the difference observed between T1 and T2 odour was not an effect of sampling time point.
This effect was independent of age, sex, temperature, or haemoglobin level at T1 of these children, indicating that the Plasmodium infection is associated with changes in odour profile that increase attraction to mosquitoes.
In a second time, researchers explored the chemical and molecular basis of these changes associated with the malaria infection.
To determine which chemical compounds in body odour would be responsible for the observed differences in attractiveness, researchers sampled again 56-foot odours from Plasmodium-infected and parasite-free Kenyan children.
Researchers created odour blends from patients harbouring similar parasite densities in order to obtain different infection profiles distinguishable by their high or low parasite density or by their absence of parasite infection.
The analysis of these extracted odours and the behavioural experiments revealed that 22 analytes whose several aldehydes such as heptanal, octanal and nonanal elicited an antennal response in Anopheles.
However, no one of these analytes was specific to any of the infection profiles, indicating that any Plasmodium-induced change in the compounds used by host-seeking Anopheles must occur by variation in the relative amounts of compounds that are present in parasite-free individuals.
Then, researchers investigated if Plasmodium infection indeed results in quantitative changes in the production of volatile compounds and they compared the profiles of 117 foot and 59 control odour samples.
Again, the samples were classed by their infection status and their parasite density when they were infected.
The analysis showed an increased of the aldehydes production such as the heptanal, octanal, nonanal, (E)-2-octénal, (E)-2-decenal and 2-octanone in infected children.
Moreover, these increases were generally associated to patients with a high parasite density and it was particularly noticeable for the heptanal, octanal and nonanal.
Thus, the levels of these 3 previous aldehydes were positively correlated with overall parasite density and this is consistent with the idea that the altered aldehyde profiles were indeed caused by malaria.
However, despite specific IACs were produced in greater amounts by individuals harboring parasites, an overall increase in volatile emissions from infected persons was not observed.
Among the IACs, the antennal response, observed to these 3 aldehydes suggests that changes in the production of these compounds could affect mosquito behaviour.
Finally, researchers studied if any of these chemical compounds could make the malaria-infected subjects more attractive to mosquitoes.
Each compound was individually added and tested at 2 different concentrations on the extracted odours from parasite-free children.
Results showed that only the heptanal at low concentration induced a behavioural response of mosquitoes suggesting that elevated emission of heptanal, at specific concentrations, by parasitemic children could contribute to their increased attractiveness to mosquitoes.
Then, researchers investigated the synergistic effects of these compounds and tested if the heptanal could induce an increased attractiveness to mosquitoes when it was associated with a synthetic mosquito lure and/or with different odour blends containing the 5 aldehydes previously identified and whose the production was associated with the parasite density in infected children.
Results showed that the only addition of heptanal didn’t increase the attractiveness of the chemical lure to mosquitoes while the aldehyde blend containing the heptanal was really attractive for mosquitoes. Moreover, the blend containing all five aldehydes did increase the attractiveness of the chemical lure.
In all cases, the increased attraction was dependent on additive effects among the infection-associated aldehydes, which are naturally present in parasite-free odour at lower concentrations. This suggests that the effects may depend on the odour blend context, a common feature of host attraction in mosquitoes.
This study is the first studying the skin odour of people naturally infected with malaria.
It shows, the production of key volatile chemicals (aldehyde compounds) by the skin is altered in people infected by malaria, and this odour change seems to be more attractive to mosquitoes.
The compounds observed to be associated to the infection could be derived from malaria-induced oxidative stress and it is possible that these aldehydes have been produced directly by the Plasmodium parasite. Indeed, a recent publication did in vitro experiments showing that red blood cells (RBCs) could produce volatiles compounds such as octanal decanal, and nonanal via interactions with components of the isoprenoid production pathway  found in Plasmodium parasites.
Thus, this mechanism and the oxidative stress mechanism would result in the observed correlation between increased parasite density and increased volatile compound production.
Even if this study can’t affirm that the increased production of IACs is under the control of malaria parasites, it could be assumed that if the parasites indirectly stimulated compound production (via triggering oxidative stress), the parasite genes underlying this stimulation would be selected for enhanced transmission, provided that the trade-off would result in a net increase in transmission.
Further studies exploring the relative costs and benefits of manipulation to the parasite are needed.
Anyway, the increased production of these aldehydes by Plasmodium-infected humans could lead an increase in mosquito biting in the natural environment and this would likely affect the transmission of malaria.
For this reason, it is necessary to continue to study these compounds which may be used to enhance the efficacy of chemical lures used to trap mosquitoes or serve as biomarkers of malaria, providing a basis for novel and non-invasive diagnostic tools.
Thanks for reading.
And don’t forget: Fight Malaria.
*Population bottleneck: Sharp reduction in the size of a population due to environmental events (such as earthquakes, floods, fires, disease, or droughts) or human activities.
**Oxidative stress: Phenomenon occurring when excess oxygen radicals are produced in cells, which could overwhelm the normal antioxidant capacity.
When the concentration of reactive species is not controlled by internal defence mechanisms such as antioxidants or enzymes involved in oxygen radical scavenging, oxidative damage occurs to proteins, lipids, and DNA, which could lead to cytotoxicity, genotoxicity, and even carcinogenesis when damaged cells can proliferate. Oxidative stress could results from the presence of xenobiotics, the activation of the immune system in response to invading microorganisms (inflammation), and radiation, which makes oxidative stress a common denominator of toxicity or stress .
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