Human Sertoli cells support high levels of Zika virus replication and persistence

Kumar, Anil; Jovel, Juan; López-Orozco, Joaquín; Limonta, Daniel; Airo, Adriana M.; Hou, Shangmei; Stryapunina, Iryna; Fibke, Chad; Moore, Ronald B.; Hobman, Tom C.

doi:10.1038/s41598-018-23899-x

Cited by 77 publications

(88 citation statements)

References 40 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].…”

supporting

confidence: 62%

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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: 62%

“…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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“…ZIKV was shown to persist in primary human foetal neural progenitors for at least 1 month with no activation of cytokine responses despite some cell death occurring [33]. Recently, a study on Sertoli cells showed that even after 6 weeks, cells were producing virions, suggesting that Sertoli cells are a major reservoir of virus [44]. In vivo studies in rhesus monkeys provide evidence of ZIKV persistence in the CNS and lymph nodes [45].…”

Section: Discussionmentioning

confidence: 99%

Basic insights into Zika virus infection of neuroglial and brain endothelial cells

Mutso

John

Ling

et al. 2020

Journal of General Virology

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Zika virus (ZIKV) has recently emerged as an important human pathogen due to the strong evidence that it causes disease of the central nervous system, particularly microcephaly and Guillain–Barré syndrome. The pathogenesis of disease, including mechanisms of neuroinvasion, may include both invasion via the blood–brain barrier and via peripheral (including cranial) nerves. Cellular responses to infection are also poorly understood. This study characterizes the in vitro infection of laboratory-adapted ZIKV African MR766 and two Asian strains of (1) brain endothelial cells (hCMEC/D3 cell line) and (2) olfactory ensheathing cells (OECs) (the neuroglia populating cranial nerve I and the olfactory bulb; both human and mouse OEC lines) in comparison to kidney epithelial cells (Vero cells, in which ZIKV infection is well characterized). Readouts included infection kinetics, intracellular virus localization, viral persistence and cytokine responses. Although not as high as in Vero cells, viral titres exceeded 104 plaque-forming units (p.f.u.) ml−1 in the endothelial/neuroglial cell types, except hOECs. Despite these substantial titres, a relatively small proportion of neuroglial cells were primarily infected. Immunolabelling of infected cells revealed localization of the ZIKV envelope and NS3 proteins in the cytoplasm; NS3 staining overlapped with that of dsRNA replication intermediate and the endoplasmic reticulum (ER). Infected OECs and endothelial cells produced high levels of pro-inflammatory chemokines. Nevertheless, ZIKV was also able to establish persistent infection in hOEC and hCMEC/D3 cells. Taken together, these results provide basic insights into ZIKV infection of endothelial and neuroglial cells and will form the basis for further study of ZIKV disease mechanisms.

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“…Other host protein involves in the cell division differentiation, proliferation and death which interact with ZIKV sfRNA are PROX1, NOVA1, TBR1, ARNT2, PRDM8, SATB2, ZNF131, ZBTB18, CPEB1, FOXP2, FMR1 and GRHL2. ZIKV is reported to cause the reproductive failure such affect spermatogenesis and placenta formation (25)(26)(27)(28)(29). The ZIKV sfRNA interacting host proteins involved in spermatogenesis are DDX4, RFX2, EXD1, RFX3 and DDX3Y; and female reproduction are CTCF, EOMES, PUM3, TP63 and SUZ12.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of sfRNA in the genome of pre-epidemic and epidemic Zika viruses for host interacting proteins potentially related to the recent epidemic

Desingu

2019

Preprint

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Zika virus (ZIKV), circulating in more than 70 countries since 2014, is causing severe developmental abnormality to compare to pre-epidemic infection. ZIKV related flaviviruses as the ability to produce subgenomic flaviviral RNAs (sfRNAs) which are associated with pathogenicity in foetal mice. This study, delineate the increased virulence of ZIKV through sfRNA mediated host protein interaction. Phylogenetically ZIKV sfRNA formed three distinct clades of African, Asian and American strains. Compare with preepidemic, the epidemic ZIKV sfRNA has genetic, RNA secondary structure and host protein interacting profile diversity. Interestingly this study found that ZIKV sfRNA interacting proteins involved in the neuronal development, differentiation, proliferation, and apoptosis along with spermatogenesis, host immunity and viral pathogenesis. The difference in the interaction profile and interaction strength between pre-epidemic and epidemic virus could be the reason for the increased virulence of the recent epidemic viruses. Targeting this protein will be the potent choice for antiviral drug designing.

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Human Sertoli cells support high levels of Zika virus replication and persistence

Cited by 77 publications

References 40 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

Basic insights into Zika virus infection of neuroglial and brain endothelial cells

Comparative analysis of sfRNA in the genome of pre-epidemic and epidemic Zika viruses for host interacting proteins potentially related to the recent epidemic

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