GENETICHTS REVEAL PF

"Genetic High Throughput Screenings by random mutagenesis to identify Plasmodium falciparum critical genes for asexual growth, sexual differentiation and virulence affecting host immune responses"

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 Obiettivo del progetto (Objective)

'Malaria is a global health problem that demands immediate practical actions to contain the high infection and mortality rates caused by Plasmodium species. Protective vaccine is still missing. Available drugs diminish their impact against Plasmodium as resistances are rising and expanding on the territories. While no vaccine of the current portfolio showed ideal protection and low-cost feasibility, drug development is still limited to formulation renewals or modifications of currently used drugs. Global health organizations committed to fight malaria identify the foremost reason of the stall on both vaccine development and drug discovery in the lack of knowledge about general mechanisms regulating the complex Plasmodium life cycle and the interactions with the host, especially with the immune system. Indeed, despite in the past few decades Plasmodium research was notably forwarded by availability of new tools, genome, microarray and proteomic data, basic and important questions on its biology are still shockingly unanswered. The field is still in great demand of approaches that allow discovering the function of ~2/3 of the genome encoded proteins. In order to respond to this need, I developed in Plasmodium falciparum a novel molecular tool for random mutagenesis that permits large scale mutant productions. This is expected to produce sortable mutants at an unprecedented frequency of 1 in 10^2 parasites by induction of a constitutively latent stable transposase. This tool is ideal to identify gene function and essentiality. By using it, we propose to investigate and characterize proteins and mechanisms i) involved in immune system-pathogen interactions; ii) critical for asexual growth and iii) essential for sexual differentiation. Our results will contribute significantly to the discovery of new targets to block Plasmodium asexual and transmission forms, and for the first time to systematically identify parasite virulence factors influencing host immune responses.'

Introduzione (Teaser)

Malaria represents a global public health concern yet detailed knowledge of the life cycle of the parasites responsible is missing. Scientists are applying novel genetic methods for insight leading to targeted treatments.

Descrizione progetto (Article)

A vaccine against malaria remains elusive and the effectiveness of existing treatments is diminishing as resistance increases. Challenges related to the development of novel therapies or preventions are largely due to a lack of understanding of the complex life cycle of the parasitic Plasmodium genus (containing several species that cause malaria), including its relationship with its host.

Plasmodium falciparum (P. falciparum) causes the most dangerous form of malaria (falciparum malaria). Scientists initiated the EU-funded project GENETICHTS REVEAL PF to apply a novel high-throughput genetic screening method to produce large-scale mutants of P. falciparum. The focus was on genes responsible for asexual growth, sexual differentiation (transmission form) and virulence through interaction with the host immune system to develop targeted therapies.

To date, scientists have made important progress in verifying the feasibility of the methods. They have induced mutagenesis in P. falciparum and are currently working on focused ways to increase mutant yield. Simultaneously, they are developing fluorescent probes that will enable sorting of mutants as they are produced, as well as assays for phenotypic defects to determine the possible role of the protein for which the mutated gene codes.

GENETICHTS REVEAL PF outcomes are expected to represent a major breakthrough in development of new treatments and possibly even a vaccine for the most dangerous form of malaria. In addition, the mutant library will be an important resource for researchers in the field. Overall, the project will make a significant contribution to the global fight against malaria.