Browsing by Author "Bento, Fabio"
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- A long noncoding RNA promotes parasite differentiation in African trypanosomesPublication . Guegan, Fabien Marc; Rajan, K. Shanmugha; Bento, Fabio; Neves, Daniel; Sequeira, Mariana; Gumińska, Natalia; Mroczek, Seweryn; Dziembowski, Andrzej; Cohen-Chalamish, Smadar; Doniger, Tirza; Galili, Beathrice; Estévez, Antonio M.; Notredame, Cedric; Michaeli, Shulamit; Figueiredo, Luisa M.The parasite Trypanosoma brucei causes African sleeping sickness that is fatal to patients if untreated. Parasite differentiation from a replicative slender form into a quiescent stumpy form promotes host survival and parasite transmission. Long noncoding RNAs (lncRNAs) are known to regulate cell differentiation in other eukaryotes. To determine whether lncRNAs are also involved in parasite differentiation, we used RNA sequencing to survey the T. brucei genome, identifying 1428 previously uncharacterized lncRNA genes. We find that grumpy lncRNA is a key regulator that promotes parasite differentiation into the quiescent stumpy form. This function is promoted by a small nucleolar RNA encoded within the grumpy lncRNA. snoGRUMPY binds to messenger RNAs of at least two stumpy regulatory genes, promoting their expression. grumpy overexpression reduces parasitemia in infected mice. Our analyses suggest that T. brucei lncRNAs modulate parasite-host interactions and provide a mechanism by which grumpy regulates cell differentiation in trypanosomes.
- Slow growing behavior in African trypanosomes during adipose tissue colonizationPublication . Trindade, Sandra; De Niz, Mariana; Sequeira, Mariana; Rebelo, Tiago; Bento, Fabio; Dejung, Mario; Narciso, Marta Valido; Escobar, Lara; Ferreira, João; Butter, Falk; Bringaud, Frédéric; Gjini, Erida; Figueiredo, Luisa M.When Trypanosoma brucei parasites, the causative agent of sleeping sickness, colonize the adipose tissue, they rewire gene expression. Whether this adaptation affects population behavior and disease treatment remained unknown. By using a mathematical model, we estimate that the population of adipose tissue forms (ATFs) proliferates slower than blood parasites. Analysis of the ATFs proteome, measurement of protein synthesis and proliferation rates confirm that the ATFs divide on average every 12 h, instead of 6 h in the blood. Importantly, the population of ATFs is heterogeneous with parasites doubling times ranging between 5 h and 35 h. Slow-proliferating parasites remain capable of reverting to the fast proliferation profile in blood conditions. Intravital imaging shows that ATFs are refractory to drug treatment. We propose that in adipose tissue, a subpopulation of T. brucei parasites acquire a slow growing behavior, which contributes to disease chronicity and treatment failure.
- Trypanosoma brucei parasites occupy and functionally adapt to the adipose tissue in micePublication . Trindade, Sandra; Rijo-Ferreira, Filipa; Carvalho, Tânia; Neves, Daniel; Guegan, Fabien Marc; Aresta-Branco, Francisco; Bento, Fabio; Young, Simon A.; Pinto, Andreia; Van Den Abbeele, Jan; Ribeiro, Ruy M.; Dias, Sérgio; Smith, Terry K.; Figueiredo, Luisa M.Trypanosoma brucei is an extracellular parasite that causes sleeping sickness. In mammalian hosts, trypanosomes are thought to exist in two major niches: early in infection, they populate the blood; later, they breach the blood-brain barrier. Working with a well-established mouse model, we discovered that adipose tissue constitutes a third major reservoir for T. brucei. Parasites from adipose tissue, here termed adipose tissue forms (ATFs), can replicate and were capable of infecting a naive animal. ATFs were transcriptionally distinct from bloodstream forms, and the genes upregulated included putative fatty acid β-oxidation enzymes. Consistent with this, ATFs were able to utilize exogenous myristate and form β-oxidation intermediates, suggesting that ATF parasites can use fatty acids as an external carbon source. These findings identify the adipose tissue as a niche for T. brucei during its mammalian life cycle and could potentially explain the weight loss associated with sleeping sickness.