Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness.
Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness.
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DOI：
10.1084/jem.20192070
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发表时间：
2021-12-06
期刊：
影响因子：
--
通讯作者：
Nombela-Arrieta C
中科院分区：
文献类型：
--
作者：
Isringhausen S;Mun Y;Kovtonyuk L;Kräutler NJ;Suessbier U;Gomariz A;Spaltro G;Helbling PM;Wong HC;Nagasawa T;Manz MG;Oxenius A;Nombela-Arrieta C
Isringhausen等人证明，慢性病毒感染导致BM间充质基质网络的持久破坏，并导致HSC竞争适应性的持久损害。IFN途径的体内阻断保护BM和HSC功能免受病毒诱导的损伤。慢性病毒感染与造血抑制、骨髓（BM）衰竭和造血干细胞（HSC）衰竭有关。然而，持续的病毒攻击和炎症反应如何靶向BM组织并扰乱造血能力仍然知之甚少。在这里，我们将联合收割机功能分析与先进的3D显微镜相结合，以证明淋巴细胞性脉络丛脑膜炎病毒的慢性感染导致（1）间充质CXCL 12丰富的网状细胞的BM基质网络的持久破坏，（2）该关键小生境子集的剩余组分的促炎转录重塑，以及（3）HSC中持久的功能缺陷和竞争适应性降低。从机制上讲，BM免疫病理学是由病毒特异性活化的CD8 T细胞引起的，其通过干扰素依赖性机制在BM中积累。I型和II型IFN途径的组合抗体介导的抑制完全抢先于CARc的变性并保护HSC免受慢性功能障碍。因此，病毒感染和随后的免疫反应通过持续降低HSC的竞争适应性和破坏必需的基质来源的造血支持线索而持久地影响BM稳态。
Isringhausen et al. demonstrate that chronic viral infection causes durable destruction of BM mesenchymal stromal networks and leads to long-lasting impairment of the competitive fitness of HSCs. In vivo blockage of IFN pathways protects BM and HSC function from viral-induced damage. 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.
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23.9
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影响因子：
4
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