STAT2-dependent restriction of Zika virus by human macrophages but not dendritic cells

Emerg Microbes Infect. 2021 Dec;10(1):1024-1037. doi: 10.1080/22221751.2021.1929503.

Abstract

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that poses significant threats to global public health. Macrophages and dendritic cells are both key sentinel cells in the host immune response and play critical roles in the pathogenesis of flavivirus infections. Recent studies showed that ZIKV could productively infect monocyte-derived dendritic cells (moDCs), but the role of macrophages in ZIKV infection remains incompletely understood. In this study, we first compared ZIKV infection in monocyte-derived macrophages (MDMs) and moDCs derived from the same donors. We demonstrated that while both MDMs and moDCs were susceptible to epidemic (Puerto Rico) and pre-epidemic (Uganda) strains of ZIKV, virus replication was largely restricted in MDMs but not in moDCs. ZIKV induced significant apoptosis in moDCs but not MDMs. The restricted virus replication in MDMs was not due to inefficient virus entry but was related to post-entry events in the viral replication cycle. In stark contrast with moDCs, ZIKV failed to inhibit STAT1 and STAT2 phosphorylation in MDMs. This resulted in the lack of efficient antagonism of the host type I interferon-mediated antiviral responses. Importantly, depletion of STAT2 but not STAT1 in MDMs significantly rescued the replication of ZIKV and the prototype flavivirus yellow fever virus. Overall, our findings revealed a differential interplay between macrophages and dendritic cells with ZIKV. While dendritic cells may be exploited by ZIKV to facilitate virus replication, macrophages restricted ZIKV infection.

Keywords: Dendritic cells; STAT1; STAT2; Zika; flavivirus; interferon signaling; macrophages.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Dendritic Cells / virology*
  • Gene Knockout Techniques
  • Humans
  • Interferon Type I / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / virology*
  • Phosphorylation
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • STAT2 Transcription Factor / genetics
  • STAT2 Transcription Factor / metabolism*
  • Vero Cells
  • Virus Replication
  • Zika Virus / physiology*
  • Zika Virus Infection / metabolism

Substances

  • Interferon Type I
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT2 protein, human

Grants and funding

This study was partly supported by funding from the Research Grants Council General Research Fund (17123920 and 17123319), the University Grants Committee, Hong Kong Special Administrative Region, China; the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for Department of Health of the Hong Kong Special Administrative Region Government; Sanming Project of Medicine in Shenzhen, China (SZSM201911014); the High Level-Hospital Program, Health Commission of Guangdong Province, China; and the Major Science and Technology Program of Hainan Province (ZDKJ202003); and the donations of Lee Wan Keung Charity Foundation Ltd, the Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, and Lo Ying Shek Chi Wai Foundation. The funding sources had no role in the study design, data collection, analysis, interpretation, or writing of the report.