Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness

• Published in: The Journal of experimental medicine 2021-12, Vol.218 (12)
• Main Authors: Isringhausen, Stephan, Mun, YeVin, Kovtonyuk, Larisa, Kräutler, Nike J, Suessbier, Ute, Gomariz, Alvaro, Spaltro, Gianluca, Helbling, Patrick M, Wong, Hui Chyn, Nagasawa, Takashi, Manz, Markus G, Oxenius, Annette, Nombela-Arrieta, César
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow - metabolism; Bone Marrow - pathology; Bone Marrow - virology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - virology; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Chronic Disease; Gene Expression Regulation; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - pathology; Hematopoietic Stem Cells - virology; Infectious disease and host defense; Interferons - metabolism; Lymphocytic Choriomeningitis - metabolism; Lymphocytic Choriomeningitis - pathology; Lymphocytic Choriomeningitis - virology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - immunology; Receptor, Interferon alpha-beta - metabolism; Stem Cells & Regeneration
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20192070

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.