Journal
NATURE MICROBIOLOGY
Volume 3, Issue 4, Pages 503-513Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41564-018-0131-9
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Funding
- National Basic Research Program of China (973 Program) [2014CB542300]
- National Natural Science Foundation of China [81101330, 31271378, 81250044, 31600659]
- Guangdong Innovative and Entrepreneurial Research Team Program [2014ZT05S136]
- Research Special Fund for Public Welfare Industry of Health [201302018]
- NIH [RO1-AI050468, RO1-DE023935, RO1-025462]
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The precise cell type hosting latent human cytomegalovirus (HCMV) remains elusive. Here, we report that HCMV reprogrammes human haematopoietic progenitor cells (HPCs) into a unique monocyte subset to achieve latency. Unlike conventional monocytes, this monocyte subset possesses higher levels of B7-H4, IL-10 and inducible nitric oxide synthase (iNOS), a longer lifespan and strong immunosuppressive capacity. Cell sorting of peripheral blood from latently infected human donors confirms that only this monocyte subset, representing less than 0.1% of peripheral mononuclear cells, is HCMV genome-positive but immediate-early-negative. Mechanistic studies demonstrate that HCMV promotes the differentiation of HPCs into this monocyte subset by activating cellular signal transducer and activator of transcription 3 (STAT3). In turn, this monocyte subset generates a high level of nitric oxide (NO) to silence HCMV immediate-early transcription and promote viral latency. By contrast, the US28-knockout HCMV mutant, which is incapable of activating STAT3, fails to reprogramme the HPCs and achieve latency. Our findings reveal that via activating the STAT3-iNOS-NO axis, HCMV differentiates human HPCs into a longevous, immunosuppressive monocyte subset for viral latency.
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