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The developmental hierarchy and scarcity of replicative slender trypanosomes in blood challenges their role in infection maintenance

The development of Trypanosoma brucei in its mammalian host is marked by a distinct morphological change as replicative “slender” forms differentiate into cell cycle arrested “stumpy” forms in a quorum-sensing-dependent manner. Although stumpy forms dominate chronic infections at the population leve...

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Autores principales: Larcombe, Stephen D., Briggs, Emma M., Savill, Nick, Szoor, Balazs, Matthews, Keith R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589647/
https://www.ncbi.nlm.nih.gov/pubmed/37824530
http://dx.doi.org/10.1073/pnas.2306848120
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author Larcombe, Stephen D.
Briggs, Emma M.
Savill, Nick
Szoor, Balazs
Matthews, Keith R.
author_facet Larcombe, Stephen D.
Briggs, Emma M.
Savill, Nick
Szoor, Balazs
Matthews, Keith R.
author_sort Larcombe, Stephen D.
collection PubMed
description The development of Trypanosoma brucei in its mammalian host is marked by a distinct morphological change as replicative “slender” forms differentiate into cell cycle arrested “stumpy” forms in a quorum-sensing-dependent manner. Although stumpy forms dominate chronic infections at the population level, the proportion of replicative parasites at the individual cell level and the irreversibility of arrest in the bloodstream are unclear. Here, we experimentally demonstrate that developmental cell cycle arrest is definitively irreversible in acute and chronic infections in mice. Furthermore, analysis of replicative capacity and single-cell transcriptome profiling reveal a temporal hierarchy, whereby cell cycle arrest and appearance of a reversible stumpy-like transcriptome precede irreversible commitment and morphological change. Unexpectedly, we show that proliferating parasites are exceptionally scarce in the blood after infections are established. This challenges the ability of bloodstream trypanosomes to sustain infection by proliferation or antigenic variation, these parasites instead being overwhelmingly adapted for transmission.
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spelling pubmed-105896472023-10-22 The developmental hierarchy and scarcity of replicative slender trypanosomes in blood challenges their role in infection maintenance Larcombe, Stephen D. Briggs, Emma M. Savill, Nick Szoor, Balazs Matthews, Keith R. Proc Natl Acad Sci U S A Biological Sciences The development of Trypanosoma brucei in its mammalian host is marked by a distinct morphological change as replicative “slender” forms differentiate into cell cycle arrested “stumpy” forms in a quorum-sensing-dependent manner. Although stumpy forms dominate chronic infections at the population level, the proportion of replicative parasites at the individual cell level and the irreversibility of arrest in the bloodstream are unclear. Here, we experimentally demonstrate that developmental cell cycle arrest is definitively irreversible in acute and chronic infections in mice. Furthermore, analysis of replicative capacity and single-cell transcriptome profiling reveal a temporal hierarchy, whereby cell cycle arrest and appearance of a reversible stumpy-like transcriptome precede irreversible commitment and morphological change. Unexpectedly, we show that proliferating parasites are exceptionally scarce in the blood after infections are established. This challenges the ability of bloodstream trypanosomes to sustain infection by proliferation or antigenic variation, these parasites instead being overwhelmingly adapted for transmission. National Academy of Sciences 2023-10-12 2023-10-17 /pmc/articles/PMC10589647/ /pubmed/37824530 http://dx.doi.org/10.1073/pnas.2306848120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Larcombe, Stephen D.
Briggs, Emma M.
Savill, Nick
Szoor, Balazs
Matthews, Keith R.
The developmental hierarchy and scarcity of replicative slender trypanosomes in blood challenges their role in infection maintenance
title The developmental hierarchy and scarcity of replicative slender trypanosomes in blood challenges their role in infection maintenance
title_full The developmental hierarchy and scarcity of replicative slender trypanosomes in blood challenges their role in infection maintenance
title_fullStr The developmental hierarchy and scarcity of replicative slender trypanosomes in blood challenges their role in infection maintenance
title_full_unstemmed The developmental hierarchy and scarcity of replicative slender trypanosomes in blood challenges their role in infection maintenance
title_short The developmental hierarchy and scarcity of replicative slender trypanosomes in blood challenges their role in infection maintenance
title_sort developmental hierarchy and scarcity of replicative slender trypanosomes in blood challenges their role in infection maintenance
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589647/
https://www.ncbi.nlm.nih.gov/pubmed/37824530
http://dx.doi.org/10.1073/pnas.2306848120
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