Genome-wide RNAi selection identifies a regulator of transmission stage-enriched gene families and cell-type differentiation in Trypanosoma brucei

Eva Rico; Alasdair Ivens; Lucy Glover; David Horn; Keith R. Matthews

doi:10.1371/journal.ppat.1006279

Genome-wide RNAi selection identifies a regulator of transmission stage-enriched gene families and cell-type differentiation in Trypanosoma brucei

Eva Rico, Alasdair Ivens, Lucy Glover, David Horn, Keith R. Matthews (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

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Abstract

Trypanosoma brucei, causing African sleeping-sickness, exploits quorum-sensing (QS) to generate the 'stumpy forms' necessary for the parasite's transmission to tsetse-flies. These quiescent cells are generated by differentiation in the bloodstream from proliferative slender forms. Using genome-wide RNAi selection we screened for repressors of transmission stage-enriched mRNAs in slender forms, using the stumpy-elevated ESAG9 transcript as a model. This identified REG9.1, whose RNAi-silencing alleviated ESAG9 repression in slender forms and tsetse-midgut procyclic forms. Interestingly, trypanosome surface protein Family 5 and Family 7 mRNAs were also elevated, which, like ESAG9, are T. brucei specific and stumpy-enriched. We suggest these contribute to the distinct transmission biology and vector tropism of T. brucei from other African trypanosome species. As well as surface family regulation, REG9.1-depletion generated QS-independent development to stumpy forms in vivo, whereas REG9.1 overexpression in bloodstream forms potentiated spontaneous differentiation to procyclic forms in the absence of an external signal. Combined, this identifies REG9.1 as a regulator of developmental cell fate, controlling the expression of Trypanosoma brucei-specific molecules elevated during transmission.

Original language	English
Article number	e1006279
Pages (from-to)	1-25
Number of pages	25
Journal	PLoS Pathogens
Volume	13
Issue number	3
DOIs	https://doi.org/10.1371/journal.ppat.1006279
Publication status	Published - 23 Mar 2017

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10.1371/journal.ppat.1006279Licence: CC BY

Final Published Version
Copyright: © 2017 Rico et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Final published version, 2.55 MBLicence: CC BY

High-Throughput Decoding of Virulence Mechanisms in African Trypanosomes (Senior Investigator Award)
Horn, D. (Investigator)
1/09/13 → 29/02/20
Project: Research

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title = "Genome-wide RNAi selection identifies a regulator of transmission stage-enriched gene families and cell-type differentiation in Trypanosoma brucei",

abstract = "Trypanosoma brucei, causing African sleeping-sickness, exploits quorum-sensing (QS) to generate the 'stumpy forms' necessary for the parasite's transmission to tsetse-flies. These quiescent cells are generated by differentiation in the bloodstream from proliferative slender forms. Using genome-wide RNAi selection we screened for repressors of transmission stage-enriched mRNAs in slender forms, using the stumpy-elevated ESAG9 transcript as a model. This identified REG9.1, whose RNAi-silencing alleviated ESAG9 repression in slender forms and tsetse-midgut procyclic forms. Interestingly, trypanosome surface protein Family 5 and Family 7 mRNAs were also elevated, which, like ESAG9, are T. brucei specific and stumpy-enriched. We suggest these contribute to the distinct transmission biology and vector tropism of T. brucei from other African trypanosome species. As well as surface family regulation, REG9.1-depletion generated QS-independent development to stumpy forms in vivo, whereas REG9.1 overexpression in bloodstream forms potentiated spontaneous differentiation to procyclic forms in the absence of an external signal. Combined, this identifies REG9.1 as a regulator of developmental cell fate, controlling the expression of Trypanosoma brucei-specific molecules elevated during transmission.",

author = "Eva Rico and Alasdair Ivens and Lucy Glover and David Horn and Matthews, {Keith R.}",

note = "This work was supported by a Wellcome Trust (https://wellcome.ac.uk) Senior Investigator award to KRM [grant number 103740/Z/14/Z], a Royal Society (https://royalsociety.org) Research merit award [grant number WM140045] to KRM, a Wellcome Trust (https://wellcome.ac.uk) Strategic Award to the Centre for Immunity, Infection and Evolution [grant number 095831], and a Wellcome Trust (https://wellcome.ac.uk) Senior Investigator Award to DH [grant number 100320/Z/12/Z].",

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AU - Matthews, Keith R.

N1 - This work was supported by a Wellcome Trust (https://wellcome.ac.uk) Senior Investigator award to KRM [grant number 103740/Z/14/Z], a Royal Society (https://royalsociety.org) Research merit award [grant number WM140045] to KRM, a Wellcome Trust (https://wellcome.ac.uk) Strategic Award to the Centre for Immunity, Infection and Evolution [grant number 095831], and a Wellcome Trust (https://wellcome.ac.uk) Senior Investigator Award to DH [grant number 100320/Z/12/Z].

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N2 - Trypanosoma brucei, causing African sleeping-sickness, exploits quorum-sensing (QS) to generate the 'stumpy forms' necessary for the parasite's transmission to tsetse-flies. These quiescent cells are generated by differentiation in the bloodstream from proliferative slender forms. Using genome-wide RNAi selection we screened for repressors of transmission stage-enriched mRNAs in slender forms, using the stumpy-elevated ESAG9 transcript as a model. This identified REG9.1, whose RNAi-silencing alleviated ESAG9 repression in slender forms and tsetse-midgut procyclic forms. Interestingly, trypanosome surface protein Family 5 and Family 7 mRNAs were also elevated, which, like ESAG9, are T. brucei specific and stumpy-enriched. We suggest these contribute to the distinct transmission biology and vector tropism of T. brucei from other African trypanosome species. As well as surface family regulation, REG9.1-depletion generated QS-independent development to stumpy forms in vivo, whereas REG9.1 overexpression in bloodstream forms potentiated spontaneous differentiation to procyclic forms in the absence of an external signal. Combined, this identifies REG9.1 as a regulator of developmental cell fate, controlling the expression of Trypanosoma brucei-specific molecules elevated during transmission.

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Genome-wide RNAi selection identifies a regulator of transmission stage-enriched gene families and cell-type differentiation in Trypanosoma brucei

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High-Throughput Decoding of Virulence Mechanisms in African Trypanosomes (Senior Investigator Award)

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