Zika virus infects human testicular tissue and germ cells

Matusali, Giulia; Houzet, Laurent; Satie, Anne‐Pascale; Mahé, Dominique; Aubry, Fabien; Couderc, Thérèse; Frouard, Julie; Bourgeau, Salomé; Bensalah, Karim; Lavoué, Sylvain; Joguet, Guillaume; Bujan, Louis; Cabie, André; Avelar, Gleide Fernandes de; Lecuit, Marc; Tortorec, Anna Le; Dejucq-Rainsford, Nathalie

doi:10.1172/jci121735

Cited by 100 publications

(126 citation statements)

References 72 publications

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“…Furthermore, previous research indicates that the viral kinetics of ZIKV in fetal sheep cells has been shown to be similar to that in immortalized Aedes albopictus cells [26]. We have also demonstrated that immortalized adult sheep kidney cells and immortalized fetal sheep testicular cells are susceptible to ZIKV infection and can sustain viral replication for many days [25].ZIKV is also unique in that sexual transmission occurs with infection of the male reproductive tract with possible establishment of prolonged, asymptomatic infection in men [27][28][29][30]. This carrier status in males may make men more likely to sexually transmit ZIKV to females than vice versa [1].…”

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confidence: 65%

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Experimental Infection of Mid-Gestation Pregnant Female and Intact Male Sheep with Zika Virus

Schwarz

Oliveira

Bonfante

et al. 2020

Viruses

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Zika virus (ZIKV) is an arbovirus that causes birth defects, persistent male infection, and sexual transmission in humans. The purpose of this study was to continue the development of an ovine ZIKV infection model; thus, two experiments were undertaken. In the first experiment, we built on previous pregnant sheep experiments by developing a mid-gestation model of ZIKV infection. Four pregnant sheep were challenged with ZIKV at 57-64 days gestation; two animals served as controls. After 13-15 days (corresponding with 70-79 days of gestation), one control and two infected animals were euthanized; the remaining animals were euthanized at 20-22 days post-infection (corresponding with 77-86 days of gestation). In the second experiment, six sexually mature, intact, male sheep were challenged with ZIKV and two animals served as controls. Infected animals were serially euthanized on days 2-6 and day 9 post-infection with the goal of isolating ZIKV from the male reproductive tract. In the mid-gestation study, virus was detected in maternal placenta and spleen, and in fetal organs, including the brains, spleens/liver, and umbilicus of infected fetuses. Fetuses from infected animals had visibly misshapen heads and morphometrics revealed significantly smaller head sizes in infected fetuses when compared to controls. Placental pathology was evident in infected dams. In the male experiment, ZIKV was detected in the spleen, liver, testes/epididymides, and accessory sex glands of infected animals. Results from both experiments indicate that mid-gestation ewes can be infected with ZIKV with subsequent disruption of fetal development and that intact male sheep are susceptible to ZIKV infection and viral dissemination and replication occurs in highly vascular tissues (including those of the male reproductive tract).Viruses 2020, 12, 291 2 of 23 and negative gestational outcomes when infection occurs during pregnancy. In humans, ZIKV is believed to result in trimester-specific effects to the fetus [2][3][4][5][6][7]. Established animal models of ZIKV infection during pregnancy that result in vertical transmission include non-human primates (NHP) and type-1 interferon/interferon receptor deficient mice. In NHP models, first trimester infection most frequently results in fetal demise and reduced fetal development even in asymptomatic mothers, while second trimester infections tend to produce fetuses with higher viral loads but greater fetal viability [8][9][10]. In all NHP models, fetal pathology ranges from mild to severe manifestations, consistent with Congenital Zika Syndrome (CZS) seen in humans [11][12][13][14][15][16]. While NHP models of ZIKV infection during pregnancy recapitulate human infection, other outbred host models can serve as surrogates when ethical and economic constraints create obstacles to the use of NHP.Sheep offer a unique animal model for translational biomedical research, and have long been used as a model for human pregnancy and fetal development due to longer gestation and comparably staged rates of fetal d...

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supporting

confidence: 65%

“…ZIKV is also unique in that sexual transmission occurs with infection of the male reproductive tract with possible establishment of prolonged, asymptomatic infection in men [27][28][29][30]. This carrier status in males may make men more likely to sexually transmit ZIKV to females than vice versa [1].…”

mentioning

confidence: 99%

Experimental Infection of Mid-Gestation Pregnant Female and Intact Male Sheep with Zika Virus

Schwarz

Oliveira

Bonfante

et al. 2020

Viruses

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“…However, LCs are the main source of testosterone in testis, and during ZIKV infection, the levels of testosterone are significantly modulated [78]. Testicular macrophages are infected by ZIKV [33], and the infection promotes an increase of mRNA transcript levels of the IFN-α and IFIT1 genes, inducing the secretion of pro-inflammatory cytokine TNF-α, IL-1α, and IL-8 and chemokines, such as GRO, IP-10, and monocyte chemoattractant protein 1 (MCP-1). These inflammatory mediators are correlated with the possibility that ZIKV infection can compromise SC barrier integrity [81].…”

Section: Zikv On Male Reproductive Tractmentioning

confidence: 99%

“…Macrophages are being called as true sentinels of testis function [28]. In addition, Matusali and colleagues have found evidence of ZIKV infection of the testicular CD163 + resident macrophages [33]. ZIKV-induced cell death of CD163 + resident macrophages could also contribute to the inflammation in testis.…”

Section: Introductionmentioning

confidence: 99%

The Cellular Impact of the ZIKA Virus on Male Reproductive Tract Immunology and Physiology

Almeida

Braz-de-Melo

Santos

et al. 2020

Cells

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Zika virus (ZIKV) has been reported by several groups as an important virus causing pathological damage in the male reproductive tract. ZIKV can infect and persist in testicular somatic and germ cells, as well as spermatozoa, leading to cell death and testicular atrophy. ZIKV has also been detected in semen samples from ZIKV-infected patients. This has huge implications for human reproduction. Global scientific efforts are being applied to understand the mechanisms related to arboviruses persistency, pathogenesis, and host cellular response to suggest a potential target to develop robust antiviral therapeutics and vaccines. Here, we discuss the cellular modulation of the immunologic and physiologic properties of the male reproductive tract environment caused by arboviruses infection, focusing on ZIKV. We also present an overview of the current vaccine effects and therapeutic targets against ZIKV infection that may impact the testis and male fertility.

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“…The testis is an immune-privilege organ with restricted drugs penetration, considered to constitute a tissue reservoir for HIV and other emerging viruses such as Zika and Ebola [1,26,27]. HIV-1 productively infects testicular T lymphocytes and resident macrophages, which are naturally localized in close proximity to the early germ cells present in the basal compartment of the seminiferous epithelium and therefore outside the blood testis/Sertoli cell barrier [27–31].…”

Section: Introductionmentioning

confidence: 99%

Potential for virus endogenization in humans through testicular germ cell infection: the case of HIV

Mahé

Matusali

Deléage

et al. 2020

Preprint

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30Viruses have colonized the germ line of our ancestors at several occasions during evolution, 31 leading to the integration in the human genome of viral sequences from over 30 retroviral 32 groups and a few non-retroviruses. Among the recently emerged viruses infecting humans, 33 several target the testis (eg HIV, Zika and Ebola viruses). Here we aimed to investigate whether 34 human testicular germ cells (TGCs) can support integration by HIV, a contemporary retrovirus 35 that started to spread in the human population during the last century. We report that albeit 36 alternative receptors enabled HIV-1 binding to TGCs, HIV virions failed to infect TGCs in 37 vitro. Nevertheless, exposure of TGCs to infected lymphocytes, naturally present in the testis 38 from HIV+ men, led to HIV-1 entry, integration and early protein expression. Similarly, cell-39 associated infection or bypassing viral entry led to HIV-1 integration in a spermatogonial cell 40 line. Using DNAscope, HIV-1 and SIV DNA were detected within a few TGCs in the testis 41 from one infected patient, one rhesus macaque and one African Green monkey in vivo. 42 Molecular landscape analysis revealed that early TGCs were enriched in HIV early co-factors 43 up to integration and had overall low antiviral defenses when compared with testicular 44 macrophages and Sertoli cells. In conclusion, our study reveals that TGCs can support the entry 45 and integration of HIV upon cell-associated infection. This could represent a way for this 46 contemporary virus to integrate our germline and become endogenous in the future, as happened 47 Importance 52 Viruses have colonized the host germ line at many occasions during evolution to eventually 53 become endogenous. Here we aimed at investigating whether human testicular germ cells 54 (TGCs) can support such viral invasion by studying HIV interactions with TGCs in vitro. Our 55 results indicate that isolated primary TGCs express alternative HIV-1 receptors allowing virions 56 binding but not entry. However, HIV-1 entered and integrated in TGCs upon cell-associated 57 infection, and produced low level of viral proteins. In vivo, HIV-1 and SIV DNA was detected 58 in a few TGCs. Molecular landscape analysis showed that TGCs have overall weak antiviral 59 defenses. Altogether, our results indicate that human TGCs can support HIV-1 early replication 60 including integration, suggesting potential for endogenization in the future generations. 61 62 63 Retroviruses have repeatedly infected the germline during our evolution and integrated their 64 DNA into the host genome , which has been passed on to the next generations by Mendelian 65 inheritance [1,2]. When not detrimental, the integration of viral sequences has led to their 66 fixation and endogenization in the population [3]. Thus, about 8% of the human genome is now 67 composed of endogenous retroviruses (ERVs), representing 31 distinct viral groups [2]. Such 68 integration, still ongoing in mammals [4], has driven the acquisition of new functions in the 69 host,...

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Zika virus infects human testicular tissue and germ cells

Cited by 100 publications

References 72 publications

Experimental Infection of Mid-Gestation Pregnant Female and Intact Male Sheep with Zika Virus

Experimental Infection of Mid-Gestation Pregnant Female and Intact Male Sheep with Zika Virus

The Cellular Impact of the ZIKA Virus on Male Reproductive Tract Immunology and Physiology

Potential for virus endogenization in humans through testicular germ cell infection: the case of HIV

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