Cargando…
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...
Autores principales: | , , , , |
---|---|
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 |
_version_ | 1785123834658029568 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10589647 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT larcombestephend thedevelopmentalhierarchyandscarcityofreplicativeslendertrypanosomesinbloodchallengestheirroleininfectionmaintenance AT briggsemmam thedevelopmentalhierarchyandscarcityofreplicativeslendertrypanosomesinbloodchallengestheirroleininfectionmaintenance AT savillnick thedevelopmentalhierarchyandscarcityofreplicativeslendertrypanosomesinbloodchallengestheirroleininfectionmaintenance AT szoorbalazs thedevelopmentalhierarchyandscarcityofreplicativeslendertrypanosomesinbloodchallengestheirroleininfectionmaintenance AT matthewskeithr thedevelopmentalhierarchyandscarcityofreplicativeslendertrypanosomesinbloodchallengestheirroleininfectionmaintenance AT larcombestephend developmentalhierarchyandscarcityofreplicativeslendertrypanosomesinbloodchallengestheirroleininfectionmaintenance AT briggsemmam developmentalhierarchyandscarcityofreplicativeslendertrypanosomesinbloodchallengestheirroleininfectionmaintenance AT savillnick developmentalhierarchyandscarcityofreplicativeslendertrypanosomesinbloodchallengestheirroleininfectionmaintenance AT szoorbalazs developmentalhierarchyandscarcityofreplicativeslendertrypanosomesinbloodchallengestheirroleininfectionmaintenance AT matthewskeithr developmentalhierarchyandscarcityofreplicativeslendertrypanosomesinbloodchallengestheirroleininfectionmaintenance |