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OOCYSTSTOP - blocking malaria transmission

ABSTRACT: The goal of OOCYSTOP is based on an innovative concept to block malaria transmission by development of new drugs that will be delivered (1) to oocysts in infected mosquitoes and (2) to early stages in human infection by the sporozoite

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Plasmodium Berghei Anka (ncbitaxon:5823)

SUBMITTER: FEDERICA FRATINI

PROVIDER: MSV000091377 | MassIVE | Tue Feb 28 01:31:00 GMT 2023

REPOSITORIES: MassIVE

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Publications

A Time Point Proteomic Analysis Reveals Protein Dynamics of Plasmodium Oocysts.

Preira Claude Marie François CMF Pizzi Elisabetta E Fratini Federica F Grasso Felicia F Boccolini Daniela D Mochi Stefania S Favia Guido G Piselli Elena E Damiani Claudia C Siden-Kiamos Inga I Ponzi Marta M Currà Chiara C

Molecular & cellular proteomics : MCP 20240210 3

The oocyst is a sporogonic stage of Plasmodium development that takes place in the mosquito midgut in about 2 weeks. The cyst is protected by a capsule of unknown composition, and little is known about oocyst biology. We carried out a proteomic analysis of oocyst samples isolated at early, mid, and late time points of development. Four biological replicates for each time point were analyzed, and almost 600 oocyst-specific candidates were identified. The analysis revealed that, in young oocysts, ...[more]

PMID: 38342407

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Project description:The main purpose of this article is to formulate a deterministic mathematical model for the transmission of malaria that considers two host types in the human population. The first type is called "non-immune" comprising all humans who have never acquired immunity against malaria and the second type is called "semi-immune". Non-immune are divided into susceptible, exposed and infectious and semi-immune are divided into susceptible, exposed, infectious and immune. We obtain an explicit formula for the reproductive number, R(0) which is a function of the weight of the transmission semi-immune-mosquito-semi-immune, R(0a), and the weight of the transmission non-immune-mosquito-non-immune, R(0e). Then, we study the existence of endemic equilibria by using bifurcation analysis. We give a simple criterion when R(0) crosses one for forward and backward bifurcation. We explore the possibility of a control for malaria through a specific sub-group such as non-immune or semi-immune or mosquitoes

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Project description:This work describes the activity of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX) and of its newly identified carboxylic acid metabolite on human malaria parasite Plasmodium falciparum. NBDHEX has been previously identified as a potent cytotoxic agent against murine and human cancer cells as well as towards the protozoan parasite Giardia duodenalis. We show here that NBDHEX is active in vitro against all blood stages of P. falciparum, with the rare feature of killing the parasite stages transmissible to mosquito, the immature and the mature gametocytes, with a 4-fold higher activity than that on the pathogenic asexual stages. This activity importantly translates into blocking parasite transmission through the Anopheles vector in mosquito experimental infections. A mass spectrometry analysis identified covalent NBDHEX modifications in specific cysteine residues of five gametocyte proteins, possibly associated to its antiparasitic effect. The carboxylic acid metabolite of NBDHEX retains the gametocyte preferential inhibitory activity of the parent compound, making this novel P. falciparum transmission blocking chemotype at least as a new tool to uncover biological processes targetable by gametocyte selective drugs. Both NBDHEX and its carboxylic acid metabolite show very limited in vitro cytotoxicity on VERO cells. This result and previous evidence that NBDHEX shows an excellent in vivo safety profile in mice and is orally active against human cancer xenografts make these molecules potential starting points to develop new P. falciparum transmission blocking agents, enriching the repertoire of drugs needed to eliminate malaria.

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Serratia_infections

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Project description:Gametocytogenesis, the process by which malaria parasites produce sexual forms that can infect mosquitoes, is essential for the transmission of malaria. A transcriptional switch of the pfap2-g gene triggers sexual commitment, but how the complex multi-step process is precisely programed remains largely unknown. Here, by systematic functional screening of a panel of ApiAP2 transcription factors, we identify six new apiAP2 members associated with gametocytogenesis in Plasmodium falciparum. Among these, PfAP2-G5 (PF3D7_1139300) was found to be indispensable for gametocytogenesis. This factor suppresses the transcriptional activity of the pfap2-g gene via binding to both the upstream region and exonic gene body, the latter is linked to the maintenance of local heterochromatin structure, thereby preventing initiation of sexual commitment. Removal of this repressive effect through pfap2-g5 knockout disrupts the asexual replication cycle and promotes sexual commitment accompanied by upregulation of pfap2-g expression. However, the gametocytes produced fail to mature fully. Further analyses show that PfAP2-G5 is essential for gametocyte maturation, and causes the down-regulation of pfap2-g and a set of early gametocyte genes activated by PfAP2-G prior to gametocyte development. Collectively, our findings reveal a regulation cascade of gametocyte production in malaria parasites, and provide a new target for transmission blocking interventions.

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