S100A4+ macrophages facilitate zika virus invasion and persistence in the seminiferous tubules via interferon-gamma mediation

PLoS Pathog. 2020 Dec 14;16(12):e1009019. doi: 10.1371/journal.ppat.1009019. eCollection 2020 Dec.

Abstract

Testicular invasion and persistence are features of Zika virus (ZIKV), but their mechanisms are still unknown. Here, we showed that S100A4+ macrophages, a myeloid macrophage subpopulation with susceptibility to ZIKV infection, facilitated ZIKV invasion and persistence in the seminiferous tubules. In ZIKV-infected mice, S100A4+ macrophages were specifically recruited into the interstitial space of testes and differentiated into interferon-γ-expressing M1 macrophages. With interferon-γ mediation, S100A4+ macrophages down-regulated Claudin-1 expression and induced its redistribution from the cytosol to nucleus, thus increasing the permeability of the blood-testis barrier which facilitated S100A4+ macrophages invasion into the seminiferous tubules. Intraluminal S100A4+ macrophages were segregated from CD8+ T cells and consequently helped ZIKV evade cellular immunity. As a result, ZIKV continued to replicate in intraluminal S100A4+ macrophages even when the spermatogenic cells disappeared. Deficiencies in S100A4 or interferon-γ signaling both reduced ZIKV infection in the seminiferous tubules. These results demonstrated crucial roles of S100A4+ macrophages in ZIKV infection in testes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Claudin-1 / genetics
  • Claudin-1 / metabolism
  • Interferon-gamma / metabolism
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • RNA, Viral
  • S100 Calcium-Binding Protein A4 / immunology*
  • S100 Calcium-Binding Protein A4 / metabolism
  • Seminiferous Tubules / virology
  • Testis / immunology
  • Testis / virology
  • Virus Replication / immunology
  • Virus Replication / physiology
  • Zika Virus / immunology
  • Zika Virus Infection / immunology*
  • Zika Virus Infection / virology

Substances

  • Claudin-1
  • Cldn1 protein, mouse
  • RNA, Viral
  • S100 Calcium-Binding Protein A4
  • S100a4 protein, mouse
  • Interferon-gamma

Grants and funding

This work was supported by the grant from the National Natural Science Foundation of China (NSFC) (http://www.nsfc.gov.cn/). NSFC grant 81871641 to P.G.W.; NSFC grant 81972979, NSFC grant 81671971 and NSFC grant U1902210 to J.A.; NSFC grant 81902048 to Z.Y.S.; NSFC grant 81772172 to H.C.; NSFC grant U1602223 to H.N.Z. This work was also supported by the Scientific Research Plan of the Beijing Municipal Education Committee (http://jw.beijing.gov.cn/) (KM201710025002) to P.G.W. and Key Project of Beijing Natural Science Foundation B (KZ201810025035) to J.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.