Abstract
BackgroundMalaria exerts a tremendous socioeconomic impact worldwide despite current control efforts, and novel disease transmission-blocking strategies are urgently needed. The Enterobacter bacterium Esp_Z, which is naturally harboured in the mosquito midgut, can inhibit the development of Plasmodium parasites prior to their invasion of the midgut epithelium through a mechanism that involves oxidative stress. Here, a multifaceted approach is used to study the tripartite interactions between the mosquito, Esp_Z and Plasmodium, towards addressing the feasibility of using sugar-baited exposure of mosquitoes to the Esp_Z bacterium for interruption of malaria transmission.MethodsThe ability of Esp_Z to colonize Anopheles gambiae midguts harbouring microbiota derived from wild mosquitoes was determined by qPCR. Upon introduction of Esp_Z via nectar feeding, the permissiveness of colonized mosquitoes to Plasmodium falciparum infection was determined, as well as the impact of Esp_Z on mosquito fitness parameters, such as longevity, number of eggs laid and number of larvae hatched. The genome of Esp_Z was sequenced, and transcriptome analyses were performed to identify bacterial genes that are important for colonization of the mosquito midgut, as well as for ROS-production. A gene expression analysis of members of the oxidative defence pathway of Plasmodium berghei was also conducted to assess the parasite’s oxidative defence response to Esp_Z exposure.ResultsEsp_Z persisted for up to 4 days in the An. gambiae midgut after introduction via nectar feeding, and was able to significantly inhibit Plasmodium sporogonic development. Introduction of this bacterium did not adversely affect mosquito fitness. Candidate genes involved in the selection of a better fit Esp_Z to the mosquito midgut environment and in its ability to condition oxidative status of its surroundings were identified, and parasite expression data indicated that Esp_Z is able to induce a partial and temporary shutdown of the ookinetes antioxidant response.ConclusionsEsp_Z is capable of inhibiting sporogonic development of Plasmodium in the presence of the mosquito’s native microbiota without affecting mosquito fitness. Several candidate bacterial genes are likely mediating midgut colonization and ROS production, and inhibition of Plasmodium development appears to involve a shutdown of the parasite’s oxidative defence system. A better understanding of the complex reciprocal tripartite interactions can facilitate the development and optimization of an Esp_Z-based malaria control strategy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1468-2) contains supplementary material, which is available to authorized users.
Highlights
Malaria exerts a tremendous socioeconomic impact worldwide despite current control efforts, and novel disease transmission-blocking strategies are urgently needed
Colonization of the Anopheles gambiae midgut by Enterobacter sp. Zambiae (Esp_Z) Esp_Z has been detected within the midguts of fieldcaught anopheline malaria vectors [10], but its capacity to persist within the mosquito following artificial introduction is not known
The midgut microflora of field-caught mosquitoes has been shown to differ markedly from its laboratory-reared counterparts [7, 34]; a cocktail of bacteria previously isolated from the same southern Zambian populations of An. arabiensis from which Esp_Z was identified was utilized [10]
Summary
Malaria exerts a tremendous socioeconomic impact worldwide despite current control efforts, and novel disease transmission-blocking strategies are urgently needed. When mosquitoes bite a Plasmodium-infected person, the ingested Plasmodium gametocytes encounter a severe bottleneck in development at the ookinete stage within the midgut, the site where most parasites are killed [4, 5]. During this infection stage, parasites encounter the mosquito midgut microbiota. The negative impact of the mosquito microbiota on Plasmodium parasites has been well documented (reviewed in [6]) and offers an attractive opportunity to further narrow the bottleneck around Plasmodium development and its transmission between humans. The potential impact of the microbiota upon Plasmodium development suggests that studying these microorganisms could improve efforts at curtailing malaria transmission
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