The recent Zika pandemic in the Americas is linked to congenital birth defects and Guillain–Barré syndrome. White blood cells (WBCs) play an important role in host immune responses early in arboviral infection. Infected WBCs can also function as ‘Trojan horses’ and carry viruses into immune-sheltered spaces, including the placenta, testes and brain. Therefore, defining which WBCs are permissive to Zika virus (ZIKV) is critical. Here, we analyse ZIKV infectivity of peripheral blood mononuclear cells (PBMCs) in vitro and from Nicaraguan Zika patients and show CD14+CD16+ monocytes are the main target of infection, with ZIKV replication detected in some dendritic cells. The frequency of CD14+ monocytes was significantly decreased, while the CD14+CD16+ monocyte population was significantly expanded during ZIKV infection compared to uninfected controls. Viral RNA was detected in PBMCs from all patients, but in serum from only a subset, suggesting PBMCs may be a reservoir for ZIKV. In Zika patients, the frequency of infected cells was lower but the percentage of infected CD14+CD16+ monocytes was significantly higher compared to dengue cases. The gene expression profile in monocytes isolated from ZIKV- and dengue virus-infected patients was comparable, except for significant differences in interferon-γ, CXCL12, XCL1, interleukin-6 and interleukin-10 levels. Thus, our study provides a detailed picture of the innate immune profile of ZIKV infection and highlights the important role of monocytes, and CD14+CD16+ monocytes in particular.
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The authors thank C. Wang for optimizing primers, probes and standards for use of the CDC qRT-PCR assay with Nicaraguan ZIKV strains and J. Waggoner for advice and technical support regarding quantitation of viral RNA using the ZCD qRT-PCR assay. The authors also thank R. Ben-Shachar for help with statistical analysis and graphs, and D. Glasner for his invaluable assistance with figure preparation. Past and present members of the study team based at the Hospital Infantil Manuel de Jesús Rivera, the National Virology Laboratory in the Centro Nacional de Diagnóstico y Referencia of the Nicaraguan Ministry of Health, and the Sustainable Sciences Institute in Managua, Nicaragua, are thanked for their dedication and high-quality work, particularly S. Argüello, W. Avilés, C. Cerpas, D. Elizondo, F. McNally, B. Moraga, F. Narváez, A. Núñez, M. de los Ángeles Pérez, M. Vega, R. Zapata and other study personnel. The authors are also grateful to the children who participated in the study and their families. This work was supported by grants U19AI118610 (to E.H.) and R33AI100186 (to A.B. and E.H.) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH).
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Nature Communications (2019)
Nature Microbiology (2017)