Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness
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- Stephan Isringhausen
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland 1
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- YeVin Mun
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland 1
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- Larisa Kovtonyuk
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland 1
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- Nike J. Kräutler
- Institute of Microbiology, ETH Zurich, Zurich, Switzerland 2
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- Ute Suessbier
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland 1
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- Alvaro Gomariz
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland 1
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- Gianluca Spaltro
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland 1
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- Patrick M. Helbling
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland 1
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- Hui Chyn Wong
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland 1
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- Takashi Nagasawa
- Department of Microbiology and Immunology, Osaka University, Osaka, Japan 3
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- Markus G. Manz
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland 1
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- Annette Oxenius
- Institute of Microbiology, ETH Zurich, Zurich, Switzerland 2
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- César Nombela-Arrieta
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland 1
説明
<jats:p>Chronic viral infections are associated with hematopoietic suppression, bone marrow (BM) failure, and hematopoietic stem cell (HSC) exhaustion. However, how persistent viral challenge and inflammatory responses target BM tissues and perturb hematopoietic competence remains poorly understood. Here, we combine functional analyses with advanced 3D microscopy to demonstrate that chronic infection with lymphocytic choriomeningitis virus leads to (1) long-lasting decimation of the BM stromal network of mesenchymal CXCL12-abundant reticular cells, (2) proinflammatory transcriptional remodeling of remaining components of this key niche subset, and (3) durable functional defects and decreased competitive fitness in HSCs. Mechanistically, BM immunopathology is elicited by virus-specific, activated CD8 T cells, which accumulate in the BM via interferon-dependent mechanisms. Combined antibody-mediated inhibition of type I and II IFN pathways completely preempts degeneration of CARc and protects HSCs from chronic dysfunction. Hence, viral infections and ensuing immune reactions durably impact BM homeostasis by persistently decreasing the competitive fitness of HSCs and disrupting essential stromal-derived, hematopoietic-supporting cues.</jats:p>
収録刊行物
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- Journal of Experimental Medicine
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Journal of Experimental Medicine 218 (12), e20192070-, 2021-10-28
Rockefeller University Press
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詳細情報 詳細情報について
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- CRID
- 1360576118710103808
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- ISSN
- 15409538
- 00221007
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- データソース種別
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- Crossref
- KAKEN