Nematode parasites are a group of pathogens widely distributed in marine and terrestrial ecosystems. They afflict humanity with usually chronic and rarely lethal diseases, as they tend to establish long-lived chronic infections being masters of host immune system manipulation.
Despite their public health and economic relevance, the research on pathogenetic mechanisms of infections and host-parasite interplay are at their infancy. The advancement in knowledge have been so far impeded by their intrinsic natural biological complexity, by the lack of funds dedicated and of proper in-vitro models as well as by the scant large scale genomic reliable data.
The project ¿Exploring the role of exosomes in host-nematode interactions using intestinal organoids¿ is aimed to develop and assess a new superior in-vitro model based on organoids to explore the role of extracellular vesicles (EVs) in host parasite interplay.
Organoids are the most advanced and powerful tool to study pathogenesis of infectious agents being a multicellular three-dimensional structure able to recapitulate the physiologic function of the organ from which they are derived. They are widely used to study host/microbiota/pathogens interactions, however applications in parasitology are still scarce. EVs are changing the paradigm of intercellular communication being an evolutionary conserved communication mechanisms even at kingdom rank. EVs traffic contents in a protected state and recently emerged as relevant players in intercellular signalling and helminths-host interactions.
Here, we selected two zoonotic parasitic nematodes to explore inflammatory and immune response during infection using organoids: the fish-born nematode Anisakis spp. agent of anisakiasis, a disease considered emerging in Europe; and the terrestrial Strongyloides spp. agent of strongiloidiasis, an important and potentially severe neglected tropical disease.
Parasitic helminths are able to elicit carcinogenic process and it is well known for intestinal and hepatic trematodes but less clear for intestinal nematodes, in particular for those that may accidentally infect humans showing aberrant migrations.
This project represents a unique opportunity and a first step to lay the base of a robust and reliable in-vitro model to explore such unknown aspect of parasitic nematodes.
The assessment of studies for non-model nematodes and especially pathogens (not-free living organisms) is fundamental to clarify important biological issues, such as mechanisms that underlie infectivity. In fact, the
use of predictive tools to explore the crosstalk between parasitic molecules and host genes could be relevant to depict general and specific mechanisms related to pathogenic behaviour, and in a broad-spectrum may favour the development of new diagnostic and screening tools based on antigen-antibody study as well as it may facilitate drugs target discovery. At comparative level, information of this kind will aid in understanding of both conserved and divergent aspects of nematode biology in biomedical research.
The proposed in-vitro model based on a superior three-dimensional structure as organoids has not been widely used to infer the interface between the host tissues and intestinal parasites, with particular regard to gastro-intestinal nematodes. In this context the present study could open the way to a series of researches on a wide array of nematodes of human health concern.
The use of organoids in helminth research is in its infancy, but it offers an exciting approach to complement other experimental systems to better understand the interactions of helminth parasites with their specific hosts at a molecular level. The opportunity that organoids provide for working with human material, and overcoming the limitations of model organisms, is also invaluable.
In term of the TRL (technology readiness level), the use of organoids in the proposed project will provide experimental fine-tuning to recreate and promote the invasion and colonization by helminth parasites, thus updating to level TRL 7 (i.e. System prototype demonstration in operational environment).
The potential impact of such kind of project to be potentially implemented in the development of new diagnostic tool for the early discovering of exposure and treatment solution for autoimmune inflammatory diseases is of great interest. It should be pointed out that exosomes may also function as protein carrier and that the deep analysis of processes mediated by exosomes may provide the basis for the identification of potential targets for the improvement of highly specific diagnostic tools for parasite-driven allergies. It may result in the development of early diagnostic biomarkers, as well as allergen-specific, preventive and therapeutic.
In fact, the available and routinely used diagnostic methods for the detection of allergy due to Anisakis (e.g. skin prick test) demonstrated to be poorly specific (somatic antigens largely share epitopes with other organisms, such as arthropods). Moreover, the importance of tracing Strongyloides spp. infections in patients have become even more important after covid19 pandemic, as such infections can turn fatal with administration of corticosteroids. Indeed, despite the study of EVs from Strongyloides will be conducted using faecal samples derived from dogs, such model will be extended to human samples to confirm the preliminary observations. For this purpose, the clinical activity of S. Gabrielli within the Diagnostic Parasitology laboratory of the Policlinico Umberto I, would give the opportunity to diagnose the parasite in subjects refereed to the laboratory for the routine parasitological analysis.