Chronic viral infections induce major disruption of bone marrow stromal cell networks and persistent loss of hematopoietic stem cell function

Abstract

Hematopoiesis is a highly demand-adapted and tightly regulated process that is sustained by a rare population of self-renewing, multipotent hematopoietic stem and progenitor cells (HSPCs) residing in specialized microenvironments within bone marrow (BM) cavities. The basic tissue infrastructure of the BM is provided by stromal cellular networks of mesenchymal, neural and vascular origin, which are critically involved in the fine regulation of different stages of hematopoiesis. Viral infections act as major stressors to the hematopoietic system, inducing massive and adaptive responses in cellular output. Albeit the effects of viral challenge and ensuing inflammatory responses on hematopoietic cells have been studied, whether viral infections alter BM stromal scaffolds and thus shape hematopoietic responses remains poorly defined. By combining conventional in vitro and in vivo assays with 3D confocal imaging, we herein investigated the structural and functional alterations imposed on the BM after a chronic infection with Lymphocytic Choriomeningitis Virus (LCMV). Our data shows that chronic LCMV infections trigger a substantial loss of BM endothelial and mesenchymal CXCL12-abundant reticular cells. Upon viral challenge, conspicuous vasodilation of BM sinusoidal vessels is induced which was followed by intense vascular remodeling and substantial disruption of extracellular matrix networks throughout the BM cavity. Major damage to BM stromal integrity is accompanied by a profound and sustained reduction in the number of both HSPCs as well as hematopoietic stem cells by phenotype. Competitive repopulation assays revealed that the remaining HSCs are additionally impaired in their repopulation capacity for prolonged times after LCMV infection. Finally, our results indicate that the observed alterations in the composition and functionality of cells in the BM are mediated by virus-specific CD8 T cells and partly dependent on the production of specific cytokines. Our observations thus indicate that chronic infections result in persistent damage to HSPC function, which might be partially explained by an impaired regulatory function of the stromal compartment of the BM.