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


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

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.

Correspondence to Jae U. Jung.

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Supplementary Information

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

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Supplementary Data 1

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

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Fig. 1: ZIKV infects CD14+ monocytes and drives the monocyte subset shift to the CD16+ non-classical subset during whole-blood infection.
Fig. 2: Different lineages of ZIKV infection of whole blood elicit differential immunomodulatory responses.
Fig. 3: Asian ZIKV preferentially targets non-classical monocytes, driving specific IL-10 expression.
Fig. 4: Pregnancy is associated with enhanced ZIKV infection and a profound monocyte-subset shift.
Fig. 5: Pregnancy exacerbates Asian-ZIKV-induced M2-skewed immunosuppression.
Fig. 6: Transcriptome analysis of blood monocytes following African or Asian ZIKV infection.