A step towards enlisting symbiotic microbes in the fight against malaria

A symbiotic microbe naturally found in Anopheles arabiensis prevents mosquitoes from transmitting the malaria parasite
A step towards enlisting symbiotic microbes in the fight against malaria

Symbiotic microbes are associated with all animals. When symbionts are stably associated with their hosts (across lifecycles or generations) they tend to enhance their own survival by helping their hosts survive (Figure 1), often rendering their hosts more resistant to infection. This interaction is used as a control mechanism against Dengue, through the bacterial symbiont Wolbachia. Wolbachia-based control is highly effective because the symbiont can self-spread and be maintained in insect vector populations by virtue of effects on host fitness and mother to offspring transmission.

Figure 1: Schematic showing the tendency for symbionts that are more vertically (mother to offspring) transmitted to be less pathogenic and even potentially mutualistic.

A similar control strategy could be transformative for malaria, but only if symbionts with the required characteristics are discovered. Studying the symbionts naturally associated with Anopheles mosquitoes is challenging for several reasons. Symbionts are often lost when mosquitos are reared in laboratory conditions.  They often occur in isolated, rare populations (or subspecies), and cannot easily be propagated outside their host. Characterization of Anopheles symbionts requires the capacity to study wild-caught mosquitoes, brought in alive from field sites for direct observation and rearing attempts in the laboratory, requiring facilities that are field-adjacent.

Being based at the International Centre for Insect Physiology and Ecology (icipe) in Kenya, my team and I could address these challenges. We started our ‘fishing expedition’ by screening mosquitoes for the bacterial symbionts known to be protective in other insect species, and also decided to investigate a lesser-studied clade of potential symbionts called microsporidians. Microsporidians are related to fungi but have lost most of the characteristics associated with this clade to specialize on living inside cells of their hosts. Many are pathogenic, but a significant number also have symbiotic tendencies. Some microsporidians in Anopheles mosquitoes had been characterized before, only because they were associated with diseased mosquitoes. We were curious about a particular microsporidian (Microsporidia MB) that hadn’t been found in mosquitoes before yet seemed to be the most common type in our sampling sites. It may have been overlooked because it didn’t cause overt disease in mosquitoes.

We needed a strategy to study live, Microsporidia MB-infected mosquitoes.  As Microsporidia MB is transmitted from mother to offspring, we collected wild mosquitos and tested them for infection by the symbiont, using the offspring that were infected for our experiments. We were struck by the fact that Microsporidia MB-infected mosquitoes had very high loads of the symbiont but also seemed very healthy, possibly even more so than their uninfected counterparts.

To determine if this symbiont had the capacity to protect mosquitoes from malaria (Plasmodium falciparum) we subjected mosquitoes to blood that had Plasmodium gametocytes (the stage infectious to mosquitoes). It was very challenging to get the offspring of wild mosquitos to feed on blood through a membrane. In addition, having infected blood and Microsporidia MB-infected mosquitoes ready at the same time wasn’t easy. Success required much of patience and determination by the students and technicians that were the backbone of this research. Repeating this experiment over and over, a trend emerged; the mosquitoes that had Microsporidia MB never became infected with Plasmodium, harboring neither Plasmodium sporozoites nor oocysts. Microsporidia MB appears to block the Plasmodium infection cycle in mosquitoes prior to Plasmodium traversing the mosquito midgut (Figure 2).

Figure 2: Schematic showing the model for Microsporidia MB-induced Plasmodium protection in Anopheles mosquitoes. In control mosquitoes the Plasmodium infection cycle is able to progress, whereas in Microsporidia MB infected mosquitoes, Plasmodium is blocked prior to traversing the mosquito midgut.

Future studies will enable us to better understand exactly how Microsporidia MB protects its host from the malaria parasite, and how we might increase levels of Microsporidia MB in wild mosquito populations, up to a prevalence where it would have a significant impact on malaria transmission.

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