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Durham University

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Publication details for Dr Brian Suarez-Mantilla

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. (2017). Proline Metabolism is Essential for Trypanosoma brucei brucei Survival in the Tsetse Vector. PLOS Pathogens 13(1): e1006158.

Author(s) from Durham

Abstract

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.