Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy

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Blood CD14+ monocytes are frontline immunomodulators categorized into classical, intermediate or non-classical subsets, and subsequently differentiated into M1 pro- or M2 anti-inflammatory macrophages on stimulation. Although the Zika virus (ZIKV) rapidly establishes viraemia, the target cells and immune responses, particularly during pregnancy, remain elusive. Furthermore, it is unknown whether African- and Asian-lineage ZIKV have different phenotypic impacts on host immune responses. Using human blood infection, we identified CD14+ monocytes as the primary target for African- or Asian-lineage ZIKV infection. When immunoprofiles of human blood infected with ZIKV were compared, a classical/intermediate monocyte-mediated M1-skewed inflammation by the African-lineage ZIKV infection was observed, in contrast to a non-classical monocyte-mediated M2-skewed immunosuppression by the Asian-lineage ZIKV infection. Importantly, infection of the blood of pregnant women revealed an enhanced susceptibility to ZIKV infection. Specifically, Asian-lineage ZIKV infection of pregnant women’s blood led to an exacerbated M2-skewed immunosuppression of non-classical monocytes in conjunction with a global suppression of type I interferon-signalling pathway and an aberrant expression of host genes associated with pregnancy complications. Also, 30 ZIKV+ sera from symptomatic pregnant patients showed elevated levels of M2-skewed immunosuppressive cytokines and pregnancy-complication-associated fibronectin-1. This study demonstrates the differential immunomodulatory responses of blood monocytes, particularly during pregnancy, on infection with different lineages of ZIKV.

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We thank M. Diamond and C. Baronti for providing the ZIKV H/PF/2013 strain, and all the healthy volunteers for blood donations. This work was partly supported by CA200422, CA180779, DE023926, AI073099, AI116585, Hastings Foundation and Fletcher Jones Foundation (J.U.J.), MH106806 (A.B.) and 2T90DE021982-06 (J.W.B.), AI28697 and 1R21AI129534-01 from the National Institute of Allergy and Infectious Diseases/National Institutes of Health (K.N.S.), and CAPES/ 88887.116627/2016-01 from Departamento de Ciência e Tecnologia (DECIT) do Ministério da Saúde do Brasil and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (P.B.).

Author information


  1. Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medical, Zilkha Neurogenetic Institute, 1501 San Pablo Street, Los Angeles, CA, 90033, USA

    • Suan-Sin Foo
    • , Weiqiang Chen
    • , James W. Bowman
    • , Lin-Chun Chang
    • , Younho Choi
    • , Ji Seung Yoo
    • , Jianning Ge
    •  & Jae U. Jung
  2. Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Zilkha Neurogenetic Institute, 1501 San Pablo Street, Los Angeles, CA, 90033, USA

    • Yen Chan
  3. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, 90095, USA

    • Genhong Cheng
  4. Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Zilkha Neurogenetic Institute, 1501 San Pablo Street, Los Angeles, CA, 90033, USA

    • Alexandre Bonnin
  5. Division of Pediatric Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, Marion Davies Children’s Health Center, 10833 LeConte Avenue, Los Angeles, CA, 90095, USA

    • Karin Nielsen-Saines
  6. Laboratório de Pesquisa Clínica em Doenças Febris Agudas, Instituto Nacional de Infectologia Evandro Chagas, FIOCRUZ, 4365 Avenida Brasil, Rio de Janeiro, RJ, 21040-360, Brazil

    • Patrícia Brasil


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S.-S.F. performed and analysed all the experiments, prepared the figures and wrote the first draft of the manuscript. W.C., Y.C., J.W.B., L.-C.C., Y.C., J.S.Y., J.G., G.C., A.B., K.N.S. and P.B. collaborated for the experimental design and interpretation. S.-S.F. and J.U.J. jointly conceived the experimental design, interpreted the results and wrote subsequent drafts of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jae U. Jung.

Electronic supplementary material

  1. Supplementary Information

    Supplementary Figures 1–11, Supplementary Tables 3 and 5, Supplementary References.

  2. Life sciences reporting summary

  3. Supplementary Data 1

    Multiplexed NanoString gene profiling (gene expression fold change relative to mock controls).