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Proline Metabolism is Essential for Trypanosoma brucei brucei Survival in the Tsetse Vector

Mantilla, Brian S.; Marchese, Letícia; Casas-Sánchez, Aitor; Dyer, Naomi A.; Ejeh, Nicholas; Biran, Marc; Bringaud, Frédéric; Lehane, Michael J.; Acosta-Serrano, Alvaro; Silber, Ariel M.

Proline Metabolism is Essential for Trypanosoma brucei brucei Survival in the Tsetse Vector Thumbnail


Brian S. Mantilla

Letícia Marchese

Aitor Casas-Sánchez

Naomi A. Dyer

Nicholas Ejeh

Marc Biran

Frédéric Bringaud

Michael J. Lehane

Alvaro Acosta-Serrano

Ariel M. Silber



Adaptation to different nutritional environments is essential for life cycle completion by all Trypanosoma brucei sub-species. In the tsetse fly vector, L-proline is among the most abundant amino acids and is mainly used by the fly for lactation and to fuel flight muscle. The procyclic (insect) stage of T. b. brucei uses L-proline as its main carbon source, relying on an efficient catabolic pathway to convert it to glutamate, and then to succinate, acetate and alanine as the main secreted end products. Here we investigated the essentiality of an undisrupted proline catabolic pathway in T. b. brucei by studying mitochondrial Δ1-pyrroline-5- carboxylate dehydrogenase (TbP5CDH), which catalyzes the irreversible conversion of gamma-glutamate semialdehyde (γGS) into L-glutamate and NADH. In addition, we provided evidence for the absence of a functional proline biosynthetic pathway. TbP5CDH expression is developmentally regulated in the insect stages of the parasite, but absent in bloodstream forms grown in vitro. RNAi down-regulation of TbP5CDH severely affected the growth of procyclic trypanosomes in vitro in the absence of glucose, and altered the metabolic flux when proline was the sole carbon source. Furthermore, TbP5CDH knocked-down cells exhibited alterations in the mitochondrial inner membrane potential (ΔΨm), respiratory control ratio and ATP production. Also, changes in the proline-glutamate oxidative capacity slightly affected the surface expression of the major surface glycoprotein EP-procyclin. In the tsetse, TbP5CDH knocked-down cells were impaired and thus unable to colonize the fly's midgut, probably due to the lack of glucose between bloodmeals. Altogether, our data show that the regulated expression of the proline metabolism pathway in T. b. brucei allows this parasite to adapt to the nutritional environment of the tsetse midgut.


Mantilla, B. S., Marchese, L., Casas-Sánchez, A., Dyer, N. A., Ejeh, N., Biran, M., …Silber, A. M. (2017). Proline Metabolism is Essential for Trypanosoma brucei brucei Survival in the Tsetse Vector. PLoS Pathogens, 13(1), Article e1006158.

Journal Article Type Article
Acceptance Date Dec 29, 2016
Online Publication Date Jan 23, 2017
Publication Date Jan 23, 2017
Deposit Date Sep 11, 2019
Publicly Available Date Sep 17, 2019
Journal PLoS Pathogens
Print ISSN 1553-7366
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 13
Issue 1
Article Number e1006158


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Copyright Statement
© 2017 Mantilla et al. This is an open<br /> access article distributed under the terms of the<br /> Creative Commons Attribution License, which<br /> permits unrestricted use, distribution, and<br /> reproduction in any medium, provided the original<br /> author and source are credited.

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