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Human cytomegalovirus reprogrammes haematopoietic progenitor cells into immunosuppressive monocytes to achieve latency

Nature Microbiology volume 3, pages 503–513 (2018)Cite this article

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Abstract

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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Fig. 1: HCMV NR-1 infection reprogrammes human CD34+ HPCs to achieve latent infection.
Fig. 2: HCMV NR-1 infection reprogrammes human CD34+ HPCs into a long-life monocyte subset at the late stage of infection.
Fig. 3: NR-1-infected CD34+ HPCs at a late stage of infection (14 dpi or later) posess a strong immunosuppressive capacity to T-cell proliferation in a manner of Mo-MDSCs but not granulocytic MDSCs.
Fig. 4: Cellular iNOS/NO induced by STAT3 activity play a critical role in suppressing HCMV IE1 expression and viral replication in HPCs.
Fig. 5: Role of STAT3 signalling pathway in modulating HPC differentiation during HCMV latent infection.
Fig. 6: US28-KO cannot establish latency in human CD34+ HPCs because it fails to activate the STAT3–iNOS–NO axis and reprogramme HPCs to an immunosuppressive monocyte subset.

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Acknowledgements

The authors thank J.L. Littrell (Georgia State University, Atlanta, GA) for critical reading and constructive discussion of the manuscript. This work was supported by grants from the National Basic Research Program of China (973 Program) (2014CB542300), the National Natural Science Foundation of China (81101330, 31271378, 81250044 and 31600659), the Guangdong Innovative and Entrepreneurial Research Team Program (No. 2014ZT05S136), the Research Special Fund for Public Welfare Industry of Health (201302018) and the NIH (RO1-AI050468, RO1-DE023935 and RO1-025462).

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  1. These authors contributed equally: Dihan Zhu, Chaoyun Pan, Jingxue Sheng and Hongwei Liang.

Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University School of Life Sciences, Nanjing, Jiangsu, China

    Dihan Zhu, Chaoyun Pan, Hongwei Liang, Zhen Bian, Chen-Yu Zhang & Ke Zen

  2. School of Public Health, University of California, Berkeley, CA, USA

    Jingxue Sheng, Phong Trang & Fenyong Liu

  3. Center for Inflammation, Infection Diseases and Immunology, Georgia State University, Atlanta, GA, USA

    Hongwei Liang, Zhen Bian, Yuan Liu & Ke Zen

  4. Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China

    Phong Trang

  5. State Key Laboratory of Virology, Wuhan University School of Life Sciences, Wuhan, Hubei, China

    Jianguo Wu

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Contributions

D.Z., C.P., J.S., H.L. and Z.B. performed the experiments. D.Z., P.T., J.W., Y.L., F.L. and K.Z. analysed the data. D.Z., F.L. and K.Z. wrote the manuscript. F.L., C.-Y.Z. and K.Z. designed the experiments.

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Correspondence to Jianguo Wu, Fenyong Liu, Chen-Yu Zhang or Ke Zen.

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Zhu, D., Pan, C., Sheng, J. et al. Human cytomegalovirus reprogrammes haematopoietic progenitor cells into immunosuppressive monocytes to achieve latency. Nat Microbiol 3, 503–513 (2018). https://doi.org/10.1038/s41564-018-0131-9

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