Unraveling the role of Trypanosoma brucei proteins in the impairment of Plasmodium infection

Funder

Organizational Unit

Publications

Excreted Trypanosoma brucei proteins inhibit Plasmodium hepatic infection

Publication . Temporão, Adriana; Sanches-Vaz, Margarida; Luís, Rafael; Nunes-Cabaço, Helena; Smith, Terry K.; Prudêncio, Miguel; Figueiredo, Luisa M.

Malaria, a disease caused by Plasmodium parasites, remains a major threat to public health globally. It is the most common disease in patients with sleeping sickness, another parasitic illness, caused by Trypanosoma brucei. We have previously shown that a T. brucei infection impairs a secondary P. berghei liver infection and decreases malaria severity in mice. However, whether this effect requires an active trypanosome infection remained unknown. Here, we show that Plasmodium liver infection can also be inhibited by the serum of a mouse previously infected by T. brucei and by total protein lysates of this kinetoplastid. Biochemical characterisation showed that the anti-Plasmodium activity of the total T. brucei lysates depends on its protein fraction, but is independent of the abundant variant surface glycoprotein. Finally, we found that the protein(s) responsible for the inhibition of Plasmodium infection is/are present within a fraction of ~350 proteins that are excreted to the bloodstream of the host. We conclude that the defence mechanism developed by trypanosomes against Plasmodium relies on protein excretion. This study opens the door to the identification of novel antiplasmodial intervention strategies.

2021Journal article

Open access

Unravelling the role of Trypanosoma brucei proteins in the impairment of Plasmodium infection

Publication . Temporão, Adriana; Figueiredo, Luísa Miranda; Prudêncio, Miguel

Malaria and sleeping sickness, infectious diseases caused by Plasmodium parasites and Trypanosoma brucei, respectively, share geographical space in sub-Saharan Africa. Malaria is not only a major threat to public health globally but also the most common infectious disease to occur in patients with sleeping sickness. The host labs have previously shown that a T. brucei infection impairs a secondary P. berghei liver infection and decreases malaria severity in mice. However, whether this effect requires an active trypanosome infection remained unknown. Here we sought to assess whether an active T. brucei infection was required for this impairment, and to unravel the mechanism behind this phenomenon. We found that Plasmodium liver infection can also be inhibited by the serum of a mouse previously infected by T. brucei and by total protein lysates of two life cycle stages of this kinetoplastid. Additionally, mice that received T. brucei total lysates were partly protected from developing severe malaria pathology. Interestingly, the presence of total lysates of T. brucei results in a decrease in the number of infected hepatocytes rather than from an impairment of intrahepatic replication of Plasmodium parasites. Surprisingly, the phenotype observed in this co-infection appears to be independent of liver damage and the of the host’simmune response. Biochemical characterization showed that the anti Plasmodium activity of the total T. brucei lysates depends on its protein fraction, but is independent of the abundant variant surface glycoprotein and other GPI-anchored proteins. Finally, we found that the protein(s) responsible for the inhibition of Plasmodium infection is/are present within a fraction of ~350 proteins that are excreted to the bloodstream of the host. We conclude that the defence mechanism developed by trypanosomes against Plasmodium relies on protein excretion. Our study paves the way to the development of novel antiplasmodial intervention strategies, based on the mechanism involved during the co-infection between T. brucei and Plasmodium.

2022-05Doctoral thesis

Open access

N6-methyladenosine in poly(A) tails stabilize VSG transcripts

Publication . Viegas, Idálio; Macedo, Juan; Serra, Lúcia; De Niz, Mariana; Temporão, Adriana; Silva Pereira, Sara; Mirza, Aashiq H.; Bergstrom, Ed; Rodrigues, Joao A.; Aresta Branco, Francisco; Jaffrey, Samie R.; Figueiredo, Luisa M.

RNA modifications are important regulators of gene expression1. In Trypanosoma brucei, transcription is polycistronic and thus most regulation happens post-transcriptionally2. N6-methyladenosine (m6A) has been detected in this parasite, but its function remains unknown3. Here we found that m6A is enriched in 342 transcripts using RNA immunoprecipitation, with an enrichment in transcripts encoding variant surface glycoproteins (VSGs). Approximately 50% of the m6A is located in the poly(A) tail of the actively expressed VSG transcripts. m6A residues are removed from the VSG poly(A) tail before deadenylation and mRNA degradation. Computational analysis revealed an association between m6A in the poly(A) tail and a 16-mer motif in the 3' untranslated region of VSG genes. Using genetic tools, we show that the 16-mer motif acts as a cis-acting motif that is required for inclusion of m6A in the poly(A) tail. Removal of this motif from the 3' untranslated region of VSG genes results in poly(A) tails lacking m6A, rapid deadenylation and mRNA degradation. To our knowledge, this is the first identification of an RNA modification in the poly(A) tail of any eukaryote, uncovering a post-transcriptional mechanism of gene regulation.

2022Journal article

Restricted access