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.