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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Claudin-1 / genetics
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Claudin-1 / metabolism
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Interferon-gamma / metabolism
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Macrophages / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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RNA, Viral
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S100 Calcium-Binding Protein A4 / immunology*
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S100 Calcium-Binding Protein A4 / metabolism
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Seminiferous Tubules / virology
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Testis / immunology
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Testis / virology
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Virus Replication / immunology
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Virus Replication / physiology
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Zika Virus / immunology
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Zika Virus Infection / immunology*
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Zika Virus Infection / virology
Substances
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Claudin-1
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Cldn1 protein, mouse
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RNA, Viral
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S100 Calcium-Binding Protein A4
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S100a4 protein, mouse
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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.