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Experimental reduction of host Plasmodium infection load affects mosquito survival.

ABSTRACT: Plasmodium transmission success depends upon the trade-off between the use of host resources to favour parasite reproduction and the negative effects on host health, which can be mediated by infection intensity. Despite its potential influence on parasite dynamics, the effects of infection intensity on both, birds and vectors, and on Plasmodium transmission success are still poorly understood. Here, we experimentally reduced the Plasmodium load in naturally infected wild house sparrows with the antimalarial primaquine to assess the effects of intensity of infection in the vertebrate hosts on Plasmodium transmission to and by mosquitoes. We monitored the survival of Culex pipiens mosquitoes throughout the development of the parasite and the infection status of the mosquitoes by analysing the head-thorax and saliva at 13 days post-exposure to birds. The proportion of mosquitoes infected by Plasmodium and the presence of Plasmodium in saliva were not associated with the medication treatment of birds. However, the experimental treatment affected vector survival with mosquitoes fed on medicated birds showing a higher survival rate than those fed on control individuals. These results provide strong experimental evidence of the impact of parasite load of vertebrate hosts on the survival probability of malaria vectors.

SUBMITTER: Gutierrez-Lopez R

PROVIDER: S-EPMC6584735 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Experimental reduction of host Plasmodium infection load affects mosquito survival.

Gutiérrez-López Rafael R Martínez-de la Puente Josué J Gangoso Laura L Yan Jiayue J Soriguer Ramón R Figuerola Jordi J

Scientific reports 20190619 1

Plasmodium transmission success depends upon the trade-off between the use of host resources to favour parasite reproduction and the negative effects on host health, which can be mediated by infection intensity. Despite its potential influence on parasite dynamics, the effects of infection intensity on both, birds and vectors, and on Plasmodium transmission success are still poorly understood. Here, we experimentally reduced the Plasmodium load in naturally infected wild house sparrows with the ...[more]

PMID: 31217438

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Project description:The overexpression of activated, myristoylated Akt in the midgut of female transgenic Anopheles stephensi results in resistance to infection with the human malaria parasite Plasmodium falciparum but also decreased lifespan. In the present study, the understanding of mitochondria-dependent midgut homeostasis has been expanded to explain this apparent paradox in an insect of major medical importance. Given that Akt signaling is essential for cell growth and survival, we hypothesized that sustained Akt activation in the mosquito midgut would alter the balance of critical pathways that control mitochondrial dynamics to enhance parasite killing at some cost to survivorship. Toxic reactive oxygen and nitrogen species (RNOS) rise to high levels in the midgut after blood feeding, due to a combination of high NO production and a decline in FOXO-dependent antioxidants. Despite an apparent increase in mitochondrial biogenesis in young females (3 d), energy deficiencies were apparent as decreased oxidative phosphorylation and increased [AMP]/[ATP] ratios. In addition, mitochondrial mass was lower and accompanied by the presence of stalled autophagosomes in the posterior midgut, a critical site for blood digestion and stem cell-mediated epithelial maintenance and repair, and by functional degradation of the epithelial barrier. By 18 d, the age at which An. stephensi would transmit P. falciparum to human hosts, mitochondrial dysfunction coupled to Akt-mediated repression of autophagy/mitophagy was more evident and midgut epithelial structure was markedly compromised. Inhibition of RNOS by co-feeding of the nitric-oxide synthase inhibitor L-NAME at infection abrogated Akt-dependent killing of P. falciparum that begins within 18 h of infection in 3-5 d old mosquitoes. Hence, Akt-induced changes in mitochondrial dynamics perturb midgut homeostasis to enhance parasite resistance and decrease mosquito infective lifespan. Further, quality control of mitochondrial function in the midgut is necessary for the maintenance of midgut health as reflected in energy homeostasis and tissue repair and renewal.

Project description:Malaria parasites require pantothenate from both human and mosquito hosts to synthesize coenzyme A (CoA). Specifically, mosquito-stage parasites cannot synthesize pantothenate de novo or take up preformed CoA from the mosquito host, making it essential for the parasite to obtain pantothenate from mosquito stores. This makes pantothenate utilization an attractive target for controlling sexual stage malaria parasites in the mosquito. CoA is synthesized from pantothenate in a multi-step pathway initiated by the enzyme pantothenate kinase (PanK). In this work, we manipulated A. stephensi PanK activity and assessed the impact of mosquito PanK activity on the development of two malaria parasite species with distinct genetics and life cycles: the human parasite Plasmodium falciparum and the mouse parasite Plasmodium yoelii yoelii 17XNL. We identified two putative A. stephensi PanK isoforms encoded by a single gene and expressed in the mosquito midgut. Using both RNAi and small molecules with reported activity against human PanK, we confirmed that A. stephensi PanK manipulation was associated with corresponding changes in midgut CoA levels. Based on these findings, we used two small molecule modulators of human PanK activity (PZ-2891, compound 7) at reported and ten-fold EC50 doses to examine the effects of manipulating A. stephensi PanK on malaria parasite infection success. Our data showed that oral provisioning of 1.3 nM and 13 nM PZ-2891 increased midgut CoA levels and significantly decreased infection success for both Plasmodium species. In contrast, oral provisioning of 62 nM and 620 nM compound 7 decreased CoA levels and significantly increased infection success for both Plasmodium species. This work establishes the A. stephensi CoA biosynthesis pathway as a potential target for broadly blocking malaria parasite development in anopheline hosts. We envision this strategy, with small molecule PanK modulators delivered to mosquitoes via attractive bait stations, working in concert with deployment of parasite-directed novel pantothenamide drugs to block parasite infection in the human host. In mosquitoes, depletion of pantothenate through manipulation to increase CoA biosynthesis is expected to negatively impact Plasmodium survival by starving the parasite of this essential nutrient. This has the potential to kill both wild type parasites and pantothenamide-resistant parasites that could develop under pantothenamide drug pressure if these compounds are used as future therapeutics for human malaria.

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Experimental reduction of host Plasmodium infection load affects mosquito survival.

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Experimental reduction of host Plasmodium infection load affects mosquito survival.

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