Characterising Trypanosoma tissue tropism: new perspectives for variant surface glycoproteins

Descrizione del progetto

Profilazione dei parassiti killer per comprendere come e quando cambiano sembianze

La tripanosomiasi africana è la causa della malattia del sonno negli esseri umani ed è responsabile di una grave patologia che colpisce il bestiame. La tripanosomiasi africana sfugge al sistema immunitario e anche a terapie e vaccini, dal momento che la sua superficie proteica parassitaria cambia periodicamente. Ciascun genotipo parassitario conta all’incirca 1 000 diversi geni di glicoproteine di superficie variabili (VSG, variant surface glycoprotein), dei quali ne viene espresso solamente uno alla volta. Alcuni studi hanno stabilito delle correlazioni tra la distribuzione tissutale e la gravità della malattia, ma rimangono molti interrogativi. TRYPTISSUE sta approfondendo i legami tra specifici tessuti ospiti e l’espressione delle VSG per acquisire informazioni su questo meccanismo elusivo e sulla progressione della malattia. Una migliore comprensione di questi aspetti potrebbe produrre armi più efficaci contro questi e altri agenti patogeni in grado di realizzare meccanismi di variazione antigenica.

Obiettivo

African trypanosomes (Trypanosoma brucei, T. congolense, and T. vivax) are extracellular parasites responsible for animal African trypanosomiasis, a livestock disease in Africa and South America that results in frequent epidemics, substantial animal mortality and economic loss. Parasites evade the host immune system through the sequential replacement of their surface coat of variant surface glycoproteins (VSGs). In T. congolense, the VSG super-family is divided into 15 phylotypes, which may have new functions beyond immune evasion. In this fellowship, we propose that VSGs may be important in tissue tropism.
Despite being considered blood parasites, African trypanosomes colonise other tissues. The extent of extravascular colonisation and its impact in parasite development remain poorly understood, even though tissue distribution is linked to disease severity and may contribute to the large phenotypic variability observed in clinical cases.
In this fellowship, I aim to study antigenic expression in distinct tissue reservoirs. First, I will characterise tissue tropism of T. congolense and T. vivax by comparing gene expression patterns of their extravascular populations. Subsequently, I will investigate the role of individual T. congolense VSG phylotypes in tissue colonisation and disease progression. To achieve this, I will establish Clustered regularly interspaced short palindromic repeats (CRISPR)-associated gene 9 (Cas9) genome editing technology for the first time in T. congolense.
I propose a multi-disciplinary approach combining computational, cell, and molecular biology to reveal species-specific adaptions to tissues and the impact that particular VSG phylotypes may have in establishing or maintaining those niches. I will show that VSGs, well known proteins in trypanosomes, play important roles in disease that go beyond the classical antigenic variation dogma.