Blanc Inter SVSE 3 - Blanc international - Sciences de la vie, de la santé et des écosystèmes : Microbiologie, immunologie, infectiosité

Impact of actin and actin-related proteins in parasitic human infections – PARACTIN

Actin: a weapon to defeat parasitic infectious diseases affecting humans

PARACTIN poses the fundamental question of how actin (and its associated proteins) is involved and regulates pathogenesis in Plasmodium falciparum (the causative agent of malaria) and in Entamoeba histolytica (amoebiasis agent)

Molecular and cellular analysis of actin functions in the fate of parasitic diseases

Our motivation is (i) determine the role of actin (nuclear and cytoplasmic) in the organization of chromosomes, regulating gene expression and organization of microfilaments during parasites invasion of cells and living tissue and (ii) to provide clinical benefits from our basic research through the identification of new molecules able to disrupt the biological activities of parasitic actin.

The project is implemented by a consortium of laboratories in France and Mexico. Our research is conducted through a detailed analysis of proteins and complexes formed by actin and its binders following their mass spectra and physicochemical properties. Live parasites are examined (using the laser-beam microscopies) to visualize in real time the dynamic changes of the cytoskeleton enriched in actin at the cortical membrane or in the nucleus. Computer screening for molecules presenting actin affinity will lead us to discover new antiparasites treatments.

The first major result of the project is to have isolated and studied protein complexes formed with actin. Either those representative of various subcellular compartments (cytoskeleton, cytoplasm, nuclei) or those formed with chromatin fragments. By genetic engineering and cell biology, we are determining the role of identified proteins (and complexes formed) firstly, on the ability of parasites to invade human cells and tissues and secondly, in expression regulation of genes important for the survival of these microbes in regard to the immune response. By structural modeling, we defined regions in parasitic actin which can be potentially recognized by compounds grouped in the National Chemical Library (CNRS) and that will be used for a molecular screening.

The importance of morbidity and mortality caused by Entamoeba histolytica and mortality caused by Plasmodium falciparum reinforces the need to develop strategies to control diseases that these parasites produce in humans. Our goal is to provide innovative new methods for prevention, for diagnosis tests and for effective and inexpensive preventive approaches. Following this project, we expect to open new avenues in these areas through a better understanding of the activity of the actin cytoskeleton in the pathogenic process.

In 18 months we have published three articles in journals of international impact (Cell Host and Microbe, Molecular and Biochemical Parasitology Parasitology). A doctoral thesis was defended. Two meetings of the consortium PARACTIN (France-Mexico) were conducted

The teams involved in this project are interested in gene expression regulation and cytoskeleton roles sustaining pathogenesis of the parasites, Plasmodium falciparum (the agent of malaria) and Entamoeba histolytica (the agent of amoebiasis). These infectious diseases affect humans and are both present and endemic in Mexico. Malaria affects 300-500 million people and 1.5-2 million people, mostly children, die every year as a result of the infection making this one of the most threatening diseases in the World. After malaria, amoebiais is the most lethal disease by a protozoan causing 50 million cases of dysentery and 100,000 deaths from liver abscesses every year. The invasive behavior of these parasites is based on three main activities: motility, adhesion to human tissues (extracellular matrix and cells) and toxic or lytic activity on human cells. Our precedent cell biology approaches have demonstrated the existence of an actin-based mechanism for invasion of human cells or tissues by both parasites. Recently, in P. falciparum, we have discovered an unprecedented role for actin showing that it accumulates at the nuclear periphery, a region that is known for heterochromatin formation that regulates expression of genes involved in pathogenesis such var genes. Actin seems to binds to var intron regions. Lower eukaryotic cells either contain only one actin isoform or isoforms with very few differences as is the case in P. falciparum and E. histolytica. The unique properties of parasite cytoskeleton and the differences in their actin, compared to the human cytoskeleton, have opened avenues for researchers to provide new tools and compounds that able to block the life cycle of these microbes without affecting human survival. With this major goal in mind we will focus our program on parasitic actin, which is the major component of the actin-based cytoskeleton and shows important divergences at the structural level compared with human actin.
This project will address the essential question of how actin (and its associated proteins) is involved in the pathogenesis in P. falciparum and E. histolytica. Our aim is (i) to study the dynamics of actin filaments, both cytoplasmic and nuclear; (ii) to determine the role of actin regulation on pathogenesis, including heterochromatin organization, gene expression regulation and microfilament organization during parasite entry into human cells or tissues and (iii) to provide clinical benefit from fundamental research by the identification of new compounds able to block cytoskeleton activities through interaction with actin from these parasites. The proposal is based on the implementation of a consortium with the participation of laboratories from France and Mexico. We particularly aim to produce mutual benefit for both communities by promoting scientific and technological cooperation between the two participating laboratories and countries. To this goal we have built a network in which each member brings a top level of expertise to propose a multidisciplinary program including the uses of modern technologies such as imaging live cell processes, epigenetic studies and screening of new anti-parasitic compounds (based on computational modelling). This project represents the first and the most comprehensive study on the role of actin in the outcome of two major infectious diseases. It will give new understanding on the process of parasite infections, and allow us to use this information to generate new approaches against parasite spread.

Project coordination

NANCY GUILLEN (INSTITUT PASTEUR) – nguillen@pasteur.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IP INSTITUT PASTEUR
IP INSTITUT PASTEUR

Help of the ANR 306,022 euros
Beginning and duration of the scientific project: - 36 Months

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