Restriction of Zika Virus Replication in Human Monocyte-Derived Macrophages by Pro-Inflammatory (M1) Polarization

Zika virus (ZIKV), a member of the Flaviviridae family, is primarily transmitted through mosquito bites, but can also spread via sexual contact and from mother to fetus. While often asymptomatic, ZIKV can lead to severe neurological conditions, including microcephaly in fetuses and Guillain–Barré Syndrome in adults. ZIKV can infect placental macrophages and fetal microglia in vivo as well as human monocytes and monocyte- derived macrophages (MDMs) in vitro. Here, we observed that both human monocytes, and MDM particularly, supported ZIKV replication without evident cytopathicity, with virions accumulating in cytoplasmic vacuoles. We also investigated whether the cytokine- induced polarization of MDMs into M1 or M2 cells affected ZIKV replication. The stimula- tion of MDMs with pro-inflammatory cytokines (interferon-γ and tumor necrosis factor-α) polarized MDMs into M1 cells, significantly reducing ZIKV replication, akin to previous observations with a human immunodeficiency virus type-1 infection. In contrast, M2 polar- ization, induced by interleukin-4, did not affect ZIKV replication in MDMs. M1 polarization selectively reduced the expression of MERTK, a TAM family putative entry receptor, and increased the expression of several interferon-stimulated genes (ISGs) previously associated with the containment of ZIKV infection; of interest, ZIKV infection transiently boosted the expression of some ISGs in M1-MDMs. These findings suggest a dual mechanism of ZIKV restriction in M1-MDMs and highlight potential antiviral strategies targeting innate immune responses.