Microparticles in human parasitic diseases: source of biomarkers and role in disease pathogenesis?

Parasitic diseases, and in particular vector borne diseases, are responsible for 17% of the estimated global burden of all infectious diseases. Malaria, leishmaniasis, yellow fever, human African trypanosomiasis (HAT) and Chagas disease are just some examples with malaria being responsible for the highest number of deaths. The pathogenesis of these diseases is usually complex and characterised by fine, and often unclear, interactions between the parasite and the host. This is the case for malaria and HAT, the two principal subjects covered in this project. Despite being very different in aetiology and pathogenesis, they are both characterised by a cerebral involvement – neurovascular syndrome in cerebral malaria (CM) and meningo-encephalitis in HAT (stage 2/S2) – which can both lead to patients’ death or long-term neurological deficits. MP are extracellular vesicles released by all cell types under physiological conditions or following cell activation or apoptosis. These vesicles carry proteins, nucleic acids and lipids derived from the plasma membrane and cytosol of their mother cell. Their increased number in the circulation in CM patients has already been shown and their role in CM pathogenesis has been proposed. Here, it is hypothesised that deciphering the protein cargo of plasma MP in CM patients might both reveal new disease biomarkers and contribute in further understanding the pathogenesis of the disease. MP cargo from CM patients with good and poor outcome after treatment will be compared to highlight proteins associated with disease severity and with prognostic potential. The most promising proteins will be further verified on a larger number of patients to determine their value as prognostic markers. Moreover, to evaluate their cellular source and their packaging into MP, the proteins of interest, together with proteins S100A8 and S100A9 highlighted in the preliminary analyses, will be investigated using an in vitro modelling of the vascular damage occurring in CM. In this project it is also postulated that, similarly to CM, MP could be involved in the mechanisms of disease progression to the meningo-encephalitic stage and in the subsequent cerebral disease occurring in HAT. To verify this hypothesis MP number and phenotype willbe evaluated in the cerebrospinal fluid of HAT patients at different stages of disease. The results obtained might reveal new features of HAT pathogenesis paving the way for future investigations. The approaches presented in this proposal are very innovative and will, without doubt, lead to major findings.

Project details

Basic Science

Apr 2017 — Sep 2017

$52,901

Italy