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Systemic Virus Infections Differentially Modulate Cell Cycle State and Functionality of Long-Term Hematopoietic Stem Cells In Vivo.

Quiescent long-term hematopoietic stem cells (LTHSCs)are efficiently activated by type I interferon(IFN-I). However, this effect remains poorly investigatedin 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.

long-term hematopoietic stem cell ; LT-HSC ; quiescence ; type I interferon ; IFN-I ; bone marrow ; virus infection ; vesicular stomatitis virus ; murine cytomegalovirus ; acute infection ; persistent infection ; bone marrow transplantation ; functional

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