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Published on: September 18, 2020
Restriction of Zika Virus Replication in Human Monocyte-Derived Macrophages by Pro-Inflammatory (M1) Polarization
Isabel Pagani1, Silvia Ghezzi1, Giulia Aimola2
1Viral Pathogenesis and Biosafety Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
Abstract:
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 stimulation 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 polarization, 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.
Insights
Zika virus (ZIKV) replicates in human macrophages. M1-polarized macrophages restrict ZIKV by reducing entry receptor MERTK and boosting antiviral interferon-stimulated genes (ISGs).
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Zika virus (ZIKV) is a Flaviviridae family member transmitted by mosquitoes, sexual contact, and vertically.
- ZIKV infection can cause severe neurological issues like microcephaly and Guillain-Barré Syndrome.
- Macrophages, including placental macrophages and monocyte-derived macrophages (MDMs), are susceptible to ZIKV infection.
Purpose of the Study:
- To investigate ZIKV replication in human monocytes and MDMs.
- To determine the effect of macrophage polarization (M1 vs. M2) on ZIKV replication.
- To elucidate the molecular mechanisms underlying ZIKV restriction in M1-polarized macrophages.
Main Methods:
- Cultured human monocytes and MDMs were infected with ZIKV.
- MDMs were polarized into M1 or M2 phenotypes using specific cytokine cocktails (IFN-γ/TNF-α for M1, IL-4 for M2).
- ZIKV replication was quantified, and gene expression (MERTK, ISGs) was analyzed using RT-qPCR and other molecular techniques.
Main Results:
- Human monocytes and particularly MDMs supported ZIKV replication without significant cell death, with virions accumulating in cytoplasmic vacuoles.
- M1 polarization of MDMs significantly reduced ZIKV replication.
- M2 polarization did not affect ZIKV replication.
- M1 polarization led to decreased MERTK expression and increased expression of interferon-stimulated genes (ISGs), some of which were transiently upregulated by ZIKV infection itself.
Conclusions:
- Human MDMs support ZIKV replication, accumulating virions in vacuoles.
- M1 polarization confers resistance to ZIKV infection in MDMs.
- Mechanisms of M1-mediated ZIKV restriction involve downregulation of MERTK and upregulation of ISGs, suggesting potential antiviral strategies targeting innate immunity.
