Paracrine IFN Response Limits ZIKV Infection in Human Sertoli Cells.

Daniel P Strange,Saguna Verma,Lisa H Cazares,Michael D Ward,Hooman Sadri-Ardekani,Tara A Kenny,Boonyanudh Jiyarom

doi:10.3389/fmicb.2021.667146

Abstract

Zika virus (ZIKV) is unique among mosquito-borne flaviviruses in its ability to be sexually transmitted. The testes have been implicated as sites of long-term ZIKV replication, and our previous studies have identified Sertoli cells (SC), the nurse cells of the seminiferous epithelium that govern spermatogenesis, as major targets of ZIKV infection. To improve our understanding of the interaction of ZIKV with human SC, we analyzed ZIKV-induced proteome changes in these cells using high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our data demonstrated that interferon (IFN) signaling was the most significantly enriched pathway and the antiviral proteins MX1 and IFIT1 were among the top upregulated proteins in SC following ZIKV infection. The dynamic between IFN response and ZIKV infection kinetics in SC remains unclear, therefore we further determined whether MX1 and IFIT1 serve as antiviral effectors against ZIKV. We found that increased levels of MX1 at the later time points of infection coincided with diminished ZIKV infection while the silencing of MX1 and IFIT1 enhanced peak ZIKV propagation in SC. Furthermore, although IFN-I exposure was found to significantly hinder ZIKV replication in SC, IFN response was attenuated in these cells as compared to other cell types. The data in this study highlight IFN-I as a driver of the antiviral state that limits ZIKV infection in SC and suggests that MX1 and IFIT1 function as antiviral effectors against ZIKV in SC. Collectively, this study provides important biological insights into the response of SC to ZIKV infection and the ability of the virus to persist in the testes.

Highlights

Zika virus (ZIKV) is the only mosquito-borne flavivirus known to be sexually transmitted and capable of establishing persistence in the male reproductive tract (Turmel et al, 2016; Hastings and Fikrig, 2017; Moreira et al, 2017), and poses new challenges for controlling ZIKV outbreaks and for developing live-attenuated vaccines
Our prior work demonstrated that ZIKV titers peaked in Sertoli cells (SC) by 72 h post-infection (Siemann et al, 2017; Strange et al, 2018a), which corresponded with the strong induction of genes involved in innate antiviral defense pathways (Strange et al, 2018a)
Reported transcriptomics analyses (Kumar et al, 2018; Strange et al, 2018a) demonstrated that SC mounted robust antiviral defense mechanisms in response to ZIKV infection through induction of various ISGs, and indicated that ZIKV may disrupt canonical pathways involved in germ cell trafficking

Summary

Introduction

Zika virus (ZIKV) is the only mosquito-borne flavivirus known to be sexually transmitted and capable of establishing persistence in the male reproductive tract (Turmel et al, 2016; Hastings and Fikrig, 2017; Moreira et al, 2017), and poses new challenges for controlling ZIKV outbreaks and for developing live-attenuated vaccines. These data collectively implicate the testes as probable sites of prolonged ZIKV replication and suggest that persistence may have short-term effects on male reproductive health Consistent with these findings in humans, ZIKV has been detected in the testes of non-human primates and immunocompromised mice following subcutaneous inoculation, causing extensive testicular damage in the latter (Govero et al, 2016; Ma et al, 2016; Osuna et al, 2016; Hirsch et al, 2017). ZIKV is persistently shed in semen (Joguet et al, 2017; Paz-Bailey et al, 2017; Bujan et al, 2020), the virus does not cause testicular pain or inflammation in humans and is cleared without apparent long-term complications These observations suggest that the testes, which are immune-privileged organs (Chen et al, 2016), can mount local antiviral defenses that eventually resolve the infection without the help of adaptive immune cells. The specific mechanisms that facilitate the eventual resolution of ZIKV from the testes remains elusive

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Conclusion