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

Abstract

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.

Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication

“…Notably, recent studies also demonstrated that myeloid cells, including specific monocyte subsets, are highly susceptible to ZIKV during pregnancy and in infants, and highlighted the fact that ZIKV can reprogram their gene expression patterns to limit antiviral immune defense. (Foo et al, 2017; Michlmayr et al, 2017). …”

Zika virus infection studies with CD34+ hematopoietic and megakaryocyte‐erythroid progenitors, red blood cells and platelets

“…69,70 Since ZIKV is known to infect cells of the GMP lineage ( Fig. S2A, available as supporting information in the online version of this paper [44][45][46][47] ), propagation in a small subset of either cell line might explain our observations. In line with this argument, EPO deprivation did not impact ZIKV propagation in the KU812Ep6 subclone suggesting that cells other than those exhibiting erythroid-like features might support infection.…”

“…75 In addition, ZIKV as well as DENV propagate in cells of the GMP lineage. [44][45][46][47][76][77][78] However, whereas DENV NS1 protein was found to activate platelets, no such effect was observed for ZIKV. 79,80 Also, since ZIKV, but not DENV, exhibits a distinct neuro-tropism, we can assume that cell tropism of viruses from the same family indeed overlaps but ultimately differs between even closely related species.…”

“…The lack of permissiveness of the tested primary hematopoietic cells was surprising considering that the closely related Dengue virus (DENV) was reported to infect CD34 + HSPCs, GLYA‐positive MEPs, megakaryocytes and supposedly also platelets . In addition, ZIKV as well as DENV propagate in cells of the GMP lineage . However, whereas DENV NS1 protein was found to activate platelets, no such effect was observed for ZIKV .…”

“…[41][42][43] ZIKV was reported to infect several white blood cells (leukocytes) namely monocytes, macrophages, and dendritic cells. [44][45][46][47] However, so far nothing is known about the infection of CD34 + HSPCs or cells of the MEP lineage by ZIKV.…”