Hirche Christoph, Frenz Theresa, Haas Simon F, Döring Marius, Borst Katharina, Tegtmeyer Pia-K, Brizic Ilija, Jordan Stefan, Keyser Kirsten, Chhatbar Chintan, Pronk Eline, Lin Shuiping, Messerle Martin, Jonjic Stipan, Falk Christine S, Trumpp Andreas, Essers Marieke A G, Kalinke Ulrich
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany.
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; "Hematopoietic Stem Cells and Stress" Group, German Cancer Research Centre (DKFZ), 69121 Heidelberg, Germany.
Cell Rep. 2017 Jun 13;19(11):2345-2356. doi: 10.1016/j.celrep.2017.05.063.
Quiescent long-term hematopoietic stem cells (LT-HSCs) are efficiently activated by type I interferon (IFN-I). However, this effect remains poorly investigated in the context of IFN-I-inducing virus infections. Here we report that both vesicular stomatitis virus (VSV) and murine cytomegalovirus (MCMV) infection induce LT-HSC activation that substantially differs from the effects triggered upon injection of synthetic IFN-I-inducing agents. In both infections, inflammatory responses had to exceed local thresholds within the bone marrow to confer LT-HSC cell cycle entry, and IFN-I receptor triggering was not critical for this activation. After resolution of acute MCMV infection, LT-HSCs returned to phenotypic quiescence. However, non-acute MCMV infection induced a sustained inflammatory milieu within the bone marrow that was associated with long-lasting impairment of LT-HSC function. In conclusion, our results show that systemic virus infections fundamentally affect LT-HSCs and that also non-acute inflammatory stimuli in bone marrow donors can affect the reconstitution potential of bone marrow transplants.
静止的长期造血干细胞（LT-HSCs）可被I型干扰素（IFN-I）有效激活。然而，在诱导IFN-I的病毒感染背景下，这种效应仍未得到充分研究。在此，我们报告水泡性口炎病毒（VSV）和小鼠巨细胞病毒（MCMV）感染均可诱导LT-HSC激活，这与注射合成IFN-I诱导剂所引发的效应有很大不同。在这两种感染中，炎症反应必须超过骨髓内的局部阈值才能使LT-HSC进入细胞周期，并且IFN-I受体触发对此激活并不关键。急性MCMV感染消退后，LT-HSCs恢复到表型静止状态。然而，非急性MCMV感染在骨髓内诱导了持续的炎症环境，这与LT-HSC功能的长期受损有关。总之，我们的结果表明全身性病毒感染从根本上影响LT-HSCs，并且骨髓供体中的非急性炎症刺激也会影响骨髓移植的重建潜力。
