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A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis

BACKGROUND: With the successful implementation of the Surviving Sepsis Campaign guidelines, post-sepsis in-hospital mortality to sepsis continues to decrease. Those who acutely survive surgical sepsis will either rapidly recover or develop a chronic critical illness (CCI). CCI is associated with adv...

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Autores principales: Darden, Dijoia B., Dong, Xiaoru, Brusko, Maigan A., Kelly, Lauren, Fenner, Brittany, Rincon, Jaimar C., Dirain, Marvin L., Ungaro, Ricardo, Nacionales, Dina C., Gauthier, Marie, Kladde, Michael, Brusko, Todd M., Bihorac, Azra, Moore, Frederick A., Loftus, Tyler, Bacher, Rhonda, Moldawer, Lyle L., Mohr, Alicia M., Efron, Philip A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415415/
https://www.ncbi.nlm.nih.gov/pubmed/34484194
http://dx.doi.org/10.3389/fimmu.2021.696536
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author Darden, Dijoia B.
Dong, Xiaoru
Brusko, Maigan A.
Kelly, Lauren
Fenner, Brittany
Rincon, Jaimar C.
Dirain, Marvin L.
Ungaro, Ricardo
Nacionales, Dina C.
Gauthier, Marie
Kladde, Michael
Brusko, Todd M.
Bihorac, Azra
Moore, Frederick A.
Loftus, Tyler
Bacher, Rhonda
Moldawer, Lyle L.
Mohr, Alicia M.
Efron, Philip A.
author_facet Darden, Dijoia B.
Dong, Xiaoru
Brusko, Maigan A.
Kelly, Lauren
Fenner, Brittany
Rincon, Jaimar C.
Dirain, Marvin L.
Ungaro, Ricardo
Nacionales, Dina C.
Gauthier, Marie
Kladde, Michael
Brusko, Todd M.
Bihorac, Azra
Moore, Frederick A.
Loftus, Tyler
Bacher, Rhonda
Moldawer, Lyle L.
Mohr, Alicia M.
Efron, Philip A.
author_sort Darden, Dijoia B.
collection PubMed
description BACKGROUND: With the successful implementation of the Surviving Sepsis Campaign guidelines, post-sepsis in-hospital mortality to sepsis continues to decrease. Those who acutely survive surgical sepsis will either rapidly recover or develop a chronic critical illness (CCI). CCI is associated with adverse long-term outcomes and 1-year mortality. Although the pathobiology of CCI remains undefined, emerging evidence suggests a post-sepsis state of pathologic myeloid activation, inducing suboptimal lymphopoiesis and erythropoiesis, as well as downstream leukocyte dysfunction. Our goal was to use single-cell RNA sequencing (scRNA-seq) to perform a detailed transcriptomic analysis of lymphoid-derived leukocytes to better understand the pathology of late sepsis. METHODS: A mixture of whole blood myeloid-enriched and Ficoll-enriched peripheral blood mononuclear cells from four late septic patients (post-sepsis day 14-21) and five healthy subjects underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq). RESULTS: We identified unique transcriptomic patterns for multiple circulating immune cell subtypes, including B- and CD4(+), CD8(+), activated CD4(+) and activated CD8(+) T-lymphocytes, as well as natural killer (NK), NKT, and plasmacytoid dendritic cells in late sepsis patients. Analysis demonstrated that the circulating lymphoid cells maintained a transcriptome reflecting immunosuppression and low-grade inflammation. We also identified transcriptomic differences between patients with bacterial versus fungal sepsis, such as greater expression of cytotoxic genes among CD8(+) T-lymphocytes in late bacterial sepsis. CONCLUSION: Circulating non-myeloid cells display a unique transcriptomic pattern late after sepsis. Non-myeloid leukocytes in particular reveal a host endotype of inflammation, immunosuppression, and dysfunction, suggesting a role for precision medicine-guided immunomodulatory therapy.
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spelling pubmed-84154152021-09-04 A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis Darden, Dijoia B. Dong, Xiaoru Brusko, Maigan A. Kelly, Lauren Fenner, Brittany Rincon, Jaimar C. Dirain, Marvin L. Ungaro, Ricardo Nacionales, Dina C. Gauthier, Marie Kladde, Michael Brusko, Todd M. Bihorac, Azra Moore, Frederick A. Loftus, Tyler Bacher, Rhonda Moldawer, Lyle L. Mohr, Alicia M. Efron, Philip A. Front Immunol Immunology BACKGROUND: With the successful implementation of the Surviving Sepsis Campaign guidelines, post-sepsis in-hospital mortality to sepsis continues to decrease. Those who acutely survive surgical sepsis will either rapidly recover or develop a chronic critical illness (CCI). CCI is associated with adverse long-term outcomes and 1-year mortality. Although the pathobiology of CCI remains undefined, emerging evidence suggests a post-sepsis state of pathologic myeloid activation, inducing suboptimal lymphopoiesis and erythropoiesis, as well as downstream leukocyte dysfunction. Our goal was to use single-cell RNA sequencing (scRNA-seq) to perform a detailed transcriptomic analysis of lymphoid-derived leukocytes to better understand the pathology of late sepsis. METHODS: A mixture of whole blood myeloid-enriched and Ficoll-enriched peripheral blood mononuclear cells from four late septic patients (post-sepsis day 14-21) and five healthy subjects underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq). RESULTS: We identified unique transcriptomic patterns for multiple circulating immune cell subtypes, including B- and CD4(+), CD8(+), activated CD4(+) and activated CD8(+) T-lymphocytes, as well as natural killer (NK), NKT, and plasmacytoid dendritic cells in late sepsis patients. Analysis demonstrated that the circulating lymphoid cells maintained a transcriptome reflecting immunosuppression and low-grade inflammation. We also identified transcriptomic differences between patients with bacterial versus fungal sepsis, such as greater expression of cytotoxic genes among CD8(+) T-lymphocytes in late bacterial sepsis. CONCLUSION: Circulating non-myeloid cells display a unique transcriptomic pattern late after sepsis. Non-myeloid leukocytes in particular reveal a host endotype of inflammation, immunosuppression, and dysfunction, suggesting a role for precision medicine-guided immunomodulatory therapy. Frontiers Media S.A. 2021-08-16 /pmc/articles/PMC8415415/ /pubmed/34484194 http://dx.doi.org/10.3389/fimmu.2021.696536 Text en Copyright © 2021 Darden, Dong, Brusko, Kelly, Fenner, Rincon, Dirain, Ungaro, Nacionales, Gauthier, Kladde, Brusko, Bihorac, Moore, Loftus, Bacher, Moldawer, Mohr and Efron https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Darden, Dijoia B.
Dong, Xiaoru
Brusko, Maigan A.
Kelly, Lauren
Fenner, Brittany
Rincon, Jaimar C.
Dirain, Marvin L.
Ungaro, Ricardo
Nacionales, Dina C.
Gauthier, Marie
Kladde, Michael
Brusko, Todd M.
Bihorac, Azra
Moore, Frederick A.
Loftus, Tyler
Bacher, Rhonda
Moldawer, Lyle L.
Mohr, Alicia M.
Efron, Philip A.
A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis
title A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis
title_full A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis
title_fullStr A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis
title_full_unstemmed A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis
title_short A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis
title_sort novel single cell rna-seq analysis of non-myeloid circulating cells in late sepsis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415415/
https://www.ncbi.nlm.nih.gov/pubmed/34484194
http://dx.doi.org/10.3389/fimmu.2021.696536
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