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Plasmodium falciparum suppresses the host immune response by inducing the synthesis of insulin-like peptides (ILPs) in the mosquito Anopheles stephensi.

ABSTRACT: The insulin-like peptides (ILPs) and their respective signaling and regulatory pathways are highly conserved across phyla. In invertebrates, ILPs regulate diverse physiological processes, including metabolism, reproduction, behavior, and immunity. We previously reported that blood feeding alone induced minimal changes in ILP expression in Anopheles stephensi. However, ingestion of a blood meal containing human insulin or Plasmodium falciparum, which can mimic insulin signaling, leads to significant increases in ILP expression in the head and midgut, suggesting a potential role for AsILPs in the regulation of P. falciparum sporogonic development. Here, we show that soluble P. falciparum products, but not LPS or zymosan, directly induced AsILP expression in immortalized A. stephensi cells in vitro. Further, AsILP expression is dependent on signaling by the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) and phosphatidylinositol 3'-kinase (PI3K)/Akt branches of the insulin/insulin-like growth factor signaling (IIS) pathway. Inhibition of P. falciparum-induced ILPs in vivo decreased parasite development through kinetically distinct effects on mosquito innate immune responses. Specifically, knockdown of AsILP4 induced early expression of immune effector genes (1-6 h after infection), a pattern associated with significantly reduced parasite abundance prior to invasion of the midgut epithelium. In contrast, knockdown of AsILP3 increased later expression of the same genes (24 h after infection), a pattern that was associated with significantly reduced oocyst development. These data suggest that P. falciparum parasites alter the expression of mosquito AsILPs to dampen the immune response and facilitate their development in the mosquito vector.

SUBMITTER: Pietri JE

PROVIDER: S-EPMC4536081 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Plasmodium falciparum suppresses the host immune response by inducing the synthesis of insulin-like peptides (ILPs) in the mosquito Anopheles stephensi.

Pietri Jose E JE Pietri Eduardo J EJ Potts Rashaun R Riehle Michael A MA Luckhart Shirley S

Developmental and comparative immunology 20150709 1

The insulin-like peptides (ILPs) and their respective signaling and regulatory pathways are highly conserved across phyla. In invertebrates, ILPs regulate diverse physiological processes, including metabolism, reproduction, behavior, and immunity. We previously reported that blood feeding alone induced minimal changes in ILP expression in Anopheles stephensi. However, ingestion of a blood meal containing human insulin or Plasmodium falciparum, which can mimic insulin signaling, leads to signific ...[more]

PMID: 26165161

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Project description:BackgroundControl of malaria parasite transmission can be enhanced by understanding which human demographic groups serve as the infectious reservoirs. Because vector biting can be heterogeneous, some infected individuals may contribute more to human-to-mosquito transmission than others. Infection prevalence peaks in school-age children, but it is not known how often they are fed upon. Genotypic profiling of human blood permits identification of individual humans who were bitten. The present investigation used this method to estimate which human demographic groups were most responsible for transmitting malaria parasites to Anopheles mosquitoes. It was hypothesized that school-age children contribute more than other demographic groups to human-to-mosquito malaria transmission.MethodsIn a region of moderate-to-high malaria incidence in southeastern Malawi, randomly selected households were surveyed to collect human demographic information and blood samples. Blood-fed, female Anopheles mosquitoes were sampled indoors from the same houses. Genomic DNA from human blood samples and mosquito blood meals of human origin was genotyped using 24 microsatellite loci. The resultant genotypes were matched to identify which individual humans were sources of blood meals. In addition, Plasmodium falciparum DNA in mosquito abdomens was detected with polymerase chain reaction. The combined results were used to identify which humans were most frequently bitten, and the P. falciparum infection prevalence in mosquitoes that resulted from these blood meals.ResultsAnopheles females selected human hosts non-randomly and fed on more than one human in 9% of the blood meals. Few humans contributed most of the blood meals to the Anopheles vector population. Children ≤ 5 years old were under-represented in mosquito blood meals while older males (31-75 years old) were over-represented. However, the largest number of malaria-infected blood meals was from school age children (6-15 years old).ConclusionsThe results support the hypothesis that humans aged 6-15 years are the most important demographic group contributing to the transmission of P. falciparum to the Anopheles mosquito vectors. This conclusion suggests that malaria control and prevention programmes should enhance efforts targeting school-age children and males.

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.

Dataset Information

Plasmodium falciparum suppresses the host immune response by inducing the synthesis of insulin-like peptides (ILPs) in the mosquito Anopheles stephensi.

Publications

Plasmodium falciparum suppresses the host immune response by inducing the synthesis of insulin-like peptides (ILPs) in the mosquito Anopheles stephensi.

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