CD14+CD16+ monocytes are the main target of Zika virus infection in peripheral blood mononuclear cells in a paediatric study in Nicaragua

Daniela Michlmayr, Paulina Andrade, Karla Gonzalez, Angel Balmaseda, Eva Harris

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.The main targets of Zika virus infection in human peripheral blood mononuclear cells are monocytes, particularly CD14(+)CD16(+) monocytes, which are expanded in Zika patients and in in vitro-infected samples.