How to please a vampire…

...or why do mosquitoes love malaria patients so much?

Dmitry Lebedev, "Biomolecule"

Over millions of years of evolution, parasites have developed fantastic adaptations to control their bizarre habitat – the host body. Pulling the strings of signaling molecules, these virtuoso puppeteers force their puppets not only to provide themselves with food, but also to create the best conditions for their reproduction and settlement. As it turned out, malarial plasmodium, which has long been known to scientists, is not alien to this tactic. In a recent article in Science, researchers have shown that one of the parasite's metabolites plays a key role in regulating the behavior of infected mosquitoes.

Malarial plasmodium is a generalized name for several species of protozoa-endoparasites from the genus Plasmodium. As befits a self-respecting endoparasite, plasmodium spends its entire life in the body of a host organism – a mosquito or a human. And, like most parasites, its life cycle, during which the parasite must confidently jump from one host to another, while deftly dodging the blows of the immune system of both, is confused beyond measure. Scientists have long known that in order to realize their intricate life cycles, many parasites have learned to control their hosts. And in some cases, natural selection has far surpassed the fantasy of Hollywood thriller writers. (How parasite puppeteers pull the strings of their puppet masters is described in the review "Manipulation. I. Parasitic manipulation" [1]).

It has already been shown that malaria mosquitoes, for unknown reasons, prefer infected people, helping the parasite to spread. Apparently, the main role in the success of malaria patients in mosquitoes is played by their smell [2], but the mechanism of its appearance has not been disclosed. Until recently.

A group of Swedish scientists who published their work in Science [3] managed to find out that one of the metabolites of malaria plasmodium plays a key role in the attractiveness of a malaria patient for mosquitoes – a substance with a tooth-crushing name (E)-4-hydroxy-3-methyl-but-2–enyl pyrophosphate (abbreviated - GBPF). It is needed by plasmodium as a precursor in the biosynthesis cycle of isopentenyl pyrophosphate and its derivative – dimethylallyl pyrophosphate. Both of these compounds are a kind of blocks for the synthesis of isoprenoids.

The biochemistry of malarial plasmodium is quite peculiar. It is understandable: life inside another organism on everything ready often leads to the loss of entire biochemical pathways from the metabolome of parasites. Almost all eukaryotes, including humans and mosquitoes, use the mevalonate pathway, which does not involve GBPF, for the synthesis of isoprenoids. But the majority of eubacteria and spores (to which plasmodium belongs) have an alternative pathway that requires the presence of the main character of the article – the metabolite of GBPF.

In general, the importance of this substance in the development of malaria infection has been known for quite a long time: back in 2007, it was shown that GBPF activates Vy2Vδ2-type T cells in the human immune system [4]. These cells are one of the most important components of antimicrobial protection, and it is not surprising that they are activated by the action of a substance specific to bacteria and eukaryotic parasites-spores. At the same time, getting into the mosquito's body, HMBPF also activates the components of its immune system and changes the composition of its intestinal microflora [5].

In order to study the effect of various Plasmodium falciparum metabolites on Anopheles gambiae mosquitoes, the researchers had to use ingenious feeders. This device consists of a blood container closed with a soft membrane that mimics human skin and is easily pierced by the proboscis of an insect. Y-shaped tubes led to the feeders, giving the mosquito a choice among several food sources.

In experiments on feeding from membrane feeders, 95% of hungry female mosquitoes (yes, it is the female mosquitoes that feed on blood, and the males are convinced vegetarians) preferred a suspension of red blood cells with the addition of HBPF to ordinary red blood cells. At the same time, in the control experiment, females preferred the suspension of erythrocytes to glucose solution and blood serum with the addition of HMBPF. Consequently, the special piquancy of the blood of patients with malaria is given not by the GBPF itself, but by the products of its metabolism by erythrocytes.

In the next series of experiments, females were more willing to choose infected red blood cells, and the amount of HMBPF that could be isolated from infected red blood cells turned out to be quite enough to noticeably increase the interest of mosquitoes in ordinary red blood cells. Scientists were able to establish that mosquitoes are attracted by both the products of the metabolism of HMBPF secreted by erythrocytes (a set of monoterpenes and aldehydes) and HMBPF itself. A significant role in attracting mosquitoes under experimental conditions is also played by CO ₂, the release of which by erythrocytes increases under the influence of HMBPF.

But still the most interesting thing was waiting for scientists ahead. It turned out that HMBPF has a complex effect on the regulation of the behavior and physiology of mosquitoes. The addition of HMBPF increased the amount of blood consumed by mosquitoes, as well as the number of oocysts and sporozoids (life stages of plasmodium) in the animal's body. The plasmodium metabolite, on the one hand, makes the mosquito more biting, on the other hand, increases its susceptibility to malaria infection, without significantly affecting its viability. Such a versatile effect of this substance on the insect's body forced scientists to analyze its effect on the expression of mosquito genes.

To do this, RNA was isolated from the mosquito body 1, 3, 6 and 24 hours after feeding with a suspension of erythrocytes with the addition of a metabolite. It turned out that the inclusion of HBPF-erythrocytes in the mosquito diet increases the expression of intestinal enzymes of the insect and a whole group of synaptically-specific genes: synaptobrevin and synoptotagmin 1, NMDA receptor type 2 and β-monooxygenase. The metabolite also affects the expression of a number of antibacterial proteins, for example, lysozyme C1 and cecropin 1. The expression of complement genes included in the complex with the TEP1 protein gene changes. All this can affect the success of the parasite's penetration and expansion in the mosquito's body.

It turns out that GBPF, on the one hand, contributes to the release of attractant substances by human red blood cells that attract mosquitoes, which forces the mosquito to eat more actively, choosing malaria patients as the preferred victim. On the other hand, getting into a mosquito, HMBPF has a complex effect on the insect's body, suppressing its immunity and creating the most favorable conditions for the reproduction of parasites in a new host. It can be said that evolution has armed the malarial plasmodium with a kind of external action hormone that controls and modifies the host mosquito's body in the right direction for the parasite.

So, the causative agent of malaria has now also fallen into the company of manipulative parasites. The expected question arises: what if the manipulation of plasmodium is not limited to the mosquito carrier at all, but extends to infected people? An exciting and scary prospect.

Literature

1. Biomolecule: "Manipulation. I. Parasitic manipulation";
2. Batista E.P., Costa E.F., Silva A.A. (2014). Anopheles darlingi (Diptera: Culicidae) displays increased attractiveness to infected individuals with Plasmodium vivax gametocytes. Parasit. Vectors. 7, 251;
3. Emami S.N., Lindberg B.G., Hua S., Hill S., Mozuraitis R., Lehmann P. et al. (2017). A key malaria metabolite modulates vector blood seeking, feeding, and susceptibility to infection. Science. 355, 1076–1080;
4. Morita C.T., Jin C., Sarikonda G., Wang H. (2007). Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vγ2Vδ2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens. Immunol. Rev. 215, 59–76;
5. Lindberg B.G., Merritt E.A., Rayl M., Liu C., Parmryd I., Olofsson B., Faye I. (2013). Immunogenic and antioxidant effects of a pathogen-associated prenyl pyrophosphate in Anopheles gambiae. PloS One. 8, e73868.

Portal "Eternal youth" http://vechnayamolodost.ru  13.03.2017