Species interactions may be investigated at the ecological but also at the molecular level. In particular, some such interactions involve species that live inside the cells of others. One very general term that was initially used to refer to all such interactions was symbiosis. Later, the term was refined to distinguish between different types of interactions covering a spectrum going from beneficial to harmful. In all cases however, the interactions of interest are those that are intimate or last long enough to influence the short and long-term survival of the species involved. It may seem that only a limited range of species would be concerned. The complete opposite is actually the case: it is now believed that almost all species, among which humans, live in close interaction with others. For the sake of simplicity, the term of symbiosis will be kept here to denote such interactions independent of their more specific type.
The main idea we wish to explore in this project is inspired by the one universal concept underlying life. This is the concept of survival. Any living organism has indeed one single objective: to remain alive and reproduce. Not only that, any living organism is driven by the need to give its descendants the chance to perpetuate themselves. As such, no organism, and more in general, no species can be considered as “good” or “bad” in itself. Such concepts arise only from the fact that resources, some of which may be shared among different species, are of limited availability. Even worse, sometimes one species may directly represent the main resource of another, although this will rarely be the only one. Conflict thus seems inevitable, and “war” among species the only way towards survival.
However, this is not true in all cases. Conflict is often observed, even actively pursued by, for instance, humans. Two striking examples that have been attracting attention lately, not necessarily in a way that is positive for us, are related to the use of antibiotics on one hand, and insecticides on the other. Yet cooperation, or at least the need to stop distinguishing between “good” (mutualistic) and “bad” (parasitic) interactions appears to be, and indeed in many circumstances is of crucial importance for survival. The two questions which we want to address are: (i) what happens to the organisms involved in “bad” interactions with others (for instance, their human hosts) when the current treatments are used, and (ii) can we find a non-violent or cooperative way to treat such diseases?
Put in this way, the question is infinitely vast. The aim will be to reach some proofs of concepts, which may then inspire others, including ourselves in a longer term, to pursue research along this line of thought. Such proofs will in themselves already require to better understand what is involved in, and what drives or influences any interspecific interaction. We propose to do it at three main levels: of regulation notably involving small RNAs, of metabolism, and of (co)evolution. In a more practical way, we want to understand the molecular basis of how certain parasites work, how they regulate their hosts and are regulated by them in order to propose possibly new ways (maybe even non-violent ways) to control the diseases they inflict.
In this project, we have chosen three particular kingdoms to study in more detail: Bacteria, Protozoa and Fungi. We wish to have a comprehensive view of the molecular mechanisms underlying their interaction with animals. We intend to generate data using model species that are studied by the Brazilian partners. Indeed, it is important to say that we already have other such collaborations in the study of the interaction of a plant (Arabidopsis thaliana) with a parasitic fungi (Trichoderma atroviride), as well as of Trypanosoma cruzi with human, Angomonas deanei with its vector insect and other parasitic fungi, which broadens our research to other kingdoms. However, those species will not be included in this proposal. Furthermore, we can include model species from other groups with whom we collaborate.
For the experimental approaches, we will start the studies using two pathogenic organisms of the Bacteria and Protozoa kingdoms as they were already the model organisms explored by each of the partners of this proposal:
- Mycoplasma hyopneumoniae is an economically devastating pathogen in the pig farming industry and has been studied by the French team for over 8 years now with a focus on metabolic network reconstruction, transcriptomic analyses and small RNA regulatory networks. The team has also investigated the transcriptomic response of epithelial cells from swine to the infection with an attenuated strain of this bacterium.
- Klebsiella pneumoniae (Kp) is an enterobacterium naturally found in the environment on the surface of plants, soil and the integument and mucous membranes of animals. Since its identification, strains that have a high potential for virulence and / or resistance to antibiotics have been described, among them carbapenemase producing K. pneumoniae (KPC).
- Toxoplasma gondii is an intensely studied protozoan parasite, causing a worldwide disease that is severe in immunosuppressed patients and pregnant women. In brazil, the genetic diversity is high and it might explain higher number of virulent cases. It is also used as a model organism due to ease of in vitro culture and genetic manipulation. The team has been investigating molecular aspects of gene expression regulation and aim to identify proteins and pathways that are essential for parasite survival. The team has the expertise on genetic manipulation to study molecular aspects.
- Plasmodium sp includes parasite species that are infective agents of malaria, a human disease that causes thousands of deaths per year, mainly of children. There are no vaccines and its treatment face the development of parasite resistance to the available anti-malarial drugs. The Brazilian partner has been investigating immunopathogenesis of malaria and aims to identify the molecular factors involved in endothelial and monocyte activation/dysfunction. In addition, changes in molecular factors in a recurrence of the infection could also be useful as immunological markers and could be investigated as new targets for treatment.
It is worth mentioning that dissecting the players involved in a pathogenic relationship among the different organisms that cause human diseases with high social and economic impacts can lead on a long-term to potential biomarkers for diagnostic or even targets for immunotherapies of diseases. From an evolutionary point of view, bacteria and protozoan parasites are interesting models for studying evolutionary processes to unveil the peculiarities associated to the different lifestyles and adaptative capacities.