Single-cell atlas of the liver myeloid compartment before and after cure of chronic viral hepatitis.

chronic infections direct-acting antiviral fine needle aspiration hepatitis C virus immune cells innate immunity liver myeloid cells single-cell RNA-sequencing viral infections

Journal

Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886

Informations de publication

Date de publication:
25 Mar 2023
Historique:
received: 03 08 2022
revised: 22 01 2023
accepted: 14 02 2023
entrez: 27 3 2023
pubmed: 28 3 2023
medline: 28 3 2023
Statut: aheadofprint

Résumé

Chronic viral infections present serious public health challenges; however, direct-acting antivirals (DAAs) are now able to cure nearly all patients infected with the hepatitis C virus (HCV), representing the only cure of a human chronic viral infection to date. DAAs provide a valuable opportunity to study immune pathways in the reversal of chronic immune failures in an in vivo human system. To leverage this opportunity, we used plate-based single-cell RNA-seq (scRNA-seq) to deeply profile myeloid cells from liver fine needle aspirates (FNAs) in HCV patients before and after DAA treatment. We comprehensively characterized liver neutrophils, eosinophils, mast cells, conventional dendritic cells (cDCs), plasmacytoid dendritic cells (pDCs), classical monocytes, non-classical monocytes, and macrophages, and defined fine-grained subpopulations of several cell types. We discovered cell-type-specific changes post-cure, including an increase in MCM7+STMN1+ proliferating CD1C+ cDCs, which may support restoration from chronic exhaustion. We observed an expected downregulation of interferon stimulated genes (ISGs) post-cure as well as an unexpected inverse relationship between pre-treatment viral load and post-cure ISG expression in each cell type, revealing a link between viral loads and sustained modifications of the host's immune system. We found an upregulation of PD-L1/L2 expression in ISG-high neutrophils and IDO1 expression in eosinophils, pinpointing cell subpopulations crucial for immune regulation. We identified three recurring gene programs shared by multiple cell types, distilling core functions of the myeloid compartment. This comprehensive scRNA-seq atlas of human liver myeloid cells in response to a cure of chronic viral infections reveals principles of liver immunity and provides immunotherapeutic insights. Chronic viral liver infections continue to be a major public health problem. Single-cell characterization of liver immune cells in hepatitis C and post-cure provides unique insights into the architecture of liver immunity contributing to the resolution of the first curable chronic viral infection of humans. Multiple layers of innate immune regulation during chronic infections and persistent immune modifications after cure are revealed. Researchers and clinicians may leverage these findings to develop methods to optimize the post-cure environment for HCV and develop novel therapeutic approaches. NCT02476617.

Sections du résumé

BACKGROUND & AIMS OBJECTIVE
Chronic viral infections present serious public health challenges; however, direct-acting antivirals (DAAs) are now able to cure nearly all patients infected with the hepatitis C virus (HCV), representing the only cure of a human chronic viral infection to date. DAAs provide a valuable opportunity to study immune pathways in the reversal of chronic immune failures in an in vivo human system.
METHODS METHODS
To leverage this opportunity, we used plate-based single-cell RNA-seq (scRNA-seq) to deeply profile myeloid cells from liver fine needle aspirates (FNAs) in HCV patients before and after DAA treatment. We comprehensively characterized liver neutrophils, eosinophils, mast cells, conventional dendritic cells (cDCs), plasmacytoid dendritic cells (pDCs), classical monocytes, non-classical monocytes, and macrophages, and defined fine-grained subpopulations of several cell types.
RESULTS RESULTS
We discovered cell-type-specific changes post-cure, including an increase in MCM7+STMN1+ proliferating CD1C+ cDCs, which may support restoration from chronic exhaustion. We observed an expected downregulation of interferon stimulated genes (ISGs) post-cure as well as an unexpected inverse relationship between pre-treatment viral load and post-cure ISG expression in each cell type, revealing a link between viral loads and sustained modifications of the host's immune system. We found an upregulation of PD-L1/L2 expression in ISG-high neutrophils and IDO1 expression in eosinophils, pinpointing cell subpopulations crucial for immune regulation. We identified three recurring gene programs shared by multiple cell types, distilling core functions of the myeloid compartment.
CONCLUSION CONCLUSIONS
This comprehensive scRNA-seq atlas of human liver myeloid cells in response to a cure of chronic viral infections reveals principles of liver immunity and provides immunotherapeutic insights.
IMPACT AND IMPLICATIONS UNASSIGNED
Chronic viral liver infections continue to be a major public health problem. Single-cell characterization of liver immune cells in hepatitis C and post-cure provides unique insights into the architecture of liver immunity contributing to the resolution of the first curable chronic viral infection of humans. Multiple layers of innate immune regulation during chronic infections and persistent immune modifications after cure are revealed. Researchers and clinicians may leverage these findings to develop methods to optimize the post-cure environment for HCV and develop novel therapeutic approaches.
CLINICAL TRIAL NUMBER BACKGROUND
NCT02476617.

Identifiants

DOI: 10.1016/j.jhep.2023.02.040 PMID: 36972796
pubmed: 36972796
pii: S0168-8278(23)00190-3
doi: 10.1016/j.jhep.2023.02.040
pii:
doi:

Banques de données

ClinicalTrials.gov
['NCT02476617']

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023. Published by Elsevier B.V.

Auteurs

Ang Cui (A)

Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: ang_cui@g.harvard.edu.

Bo Li (B)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard University Virology Program, Harvard Medical School, Boston, MA, USA.

Michael S Wallace (MS)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Anna L K Gonye (ALK)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Christopher Oetheimer (C)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Hailey Patel (H)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Pierre Tonnerre (P)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Institut de Recherche Saint-Louis, Université Paris Cité, Inserm U976 (HIPI), Team ATIP-Avenir, Paris, France.

Jacinta A Holmes (JA)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia.

David Lieb (D)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Brianna S Yao (BS)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Aileen Ma (A)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Kela Roberts (K)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Marcos Damasio (M)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Jonathan H Chen (JH)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

Daphnee Piou (D)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Charles Carlton-Smith (C)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Joelle Brown (J)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Ravi Mylvaganam (R)

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

Jeremy Man Hon Fung (JM)

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

Moshe Sade-Feldman (M)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Jasneet Aneja (J)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Jenna Gustafson (J)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Eliana T Epstein (ET)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Shadi Salloum (S)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Cynthia Brisac (C)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Ashraf Thabet (A)

Department of Interventional Radiology, Massachusetts General Hospital, Boston, MA, USA.

Arthur Y Kim (AY)

Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Georg M Lauer (GM)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Nir Hacohen (N)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: nhacohen@mgh.harvard.edu.

Raymond T Chung (RT)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: chung.raymond@mgh.harvard.edu.

Nadia Alatrakchi (N)

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: nalatrakchi@mgh.harvard.edu.

Classifications MeSH