Zika Virus Trafficking and Interactions in the Human Male Reproductive Tract

Silva, Lucia Regina Cangussu da

doi:10.3390/pathogens7020051

Cited by 7 publications

(7 citation statements)

References 122 publications

(180 reference statements)

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“…In ruminants, some placental mineralization may occur in normal animals due to the high cellular turnover in this tissue, but grading schemes for degree of calcification, which predict disease, are not available [83]. Nonetheless, calcification of placenta, as a pathological finding has been associated with BDV gestational infections in the ewe [84]. Although our findings are qualitative, the placental calcification observed in this current study is abundant in the infected ewes for the gestational age of the infected fetuses.…”

Section: Discussionmentioning

confidence: 50%

“…Furthermore, male to female transmission is thought to play an important role in ZIKV transmission amongst humans [82,[84][85][86][87]. Previously published studies have indicated that ZIKV has many cellular targets within the male reproductive tract [28,29,34,35,84]. Since asymptomatic male infection represents an important risk factor for sexual transmission of ZIKV, feasible and translatable animal models are needed to study the effects of ZIKV infection on male reproductive organs.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

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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“…Given indications that ZIKV dissemination to neural and reproductive tissues contributes to neurologic disease and enhanced transmission dynamics 30 , 31 , and guided by previous reports of ZIKV tropism in macaques 11 , 13 , 32 , we searched for viral RNA in a variety of tissues and in semen to evaluate viral distribution in these sites. Relative to nondepleted animals, CD8-depleted cynomolgus macaques had higher levels of ZIKV RNA in the inguinal, mesenteric, and colonic lymph nodes, as well as in the spleen (Fig.…”

Section: Resultsmentioning

confidence: 99%

Immune outcomes of Zika virus infection in nonhuman primates

Schouest

Fahlberg

Scheef

et al. 2020

Sci Rep

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Although the Zika virus (ZIKV) epidemic is subsiding, immune responses that are important for controlling acute infection have not been definitively characterized. Nonhuman primate (NHP) models were rapidly developed to understand the disease and to test vaccines, and these models have since provided an understanding of the immune responses that correlate with protection during natural infection and vaccination. Here, we infected a small group of male rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) macaques with a minimally passaged Brazilian ZIKV isolate and used multicolor flow cytometry and transcriptional profiling to describe early immune patterns following infection. We found evidence of strong innate antiviral responses together with induction of neutralizing antibodies and T cell responses. We also assessed the relative importance of CD8 T cells in controlling infection by carrying out CD8 T cell depletion in an additional two animals of each species. CD8 depletion appeared to dysregulate early antiviral responses and possibly increase viral persistence, but the absence of CD8 T cells ultimately did not impair control of the virus. Together, these data describe immunological trends in two NHP species during acute ZIKV infection, providing an account of early responses that may be important in controlling infection. Zika virus (ZIKV) has been a known pathogen for over half a century 1, but severe disease manifestations were not directly associated with the virus for most of its history. The recent outbreaks of ZIKV in the Western hemisphere became linked to neurologic and congenital syndromes that have provided strong incentives to develop prophylactic and therapeutic countermeasures. Several vaccine candidates spanning multiple platforms have performed well in preclinical studies and have advanced to clinical trials, but the waning of the epidemic has precluded efficacy testing in large populations 2,3. Additionally, an understanding of the immune responses that provide protection during natural infection is not yet complete, which also complicates our ability to evaluate whether vaccines will replicate these protective responses. The immunology of ZIKV infection has been most extensively studied in mice, and murine studies have shown the critical importance of type-I interferon (IFN) in limiting disease together with the protective roles of humoral and T cell responses 4-7. A growing body of literature also describes immune responses following ZIKV infection in nonhuman primates (NHPs), which are often used in preclinical vaccine studies 8 given their genetic and immunologic similarities to humans. Multiple species of macaques have been utilized, and these models replicate clinical aspects of viral infection and disease 9-13. However, the relative importance of innate and adaptive responses in controlling infection in monkeys is only beginning to be explored in depth, and this data is an important open question for the evaluation of candidate vaccines. Here, we carried out a descriptive anal...

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“…Axl receptors are thought to be the main access route of ZIKV to immune-privileged sites, like the human male reproductive tract. Similarly to what has been observed in the brain, it is hypothesized that ZIKV particles persisting in the blood could enter the endothelium cells of capillaries in the testis, which are known to have several receptors for flaviviruses (including Axl) replicate inside them and be released in the interstitial space in contact with Leydig cells, macrophages, dendritic cells, and fibroblast [50].…”

Section: Zikv Infection and Male Fertility: Spermatogenesis And Endocmentioning

confidence: 90%

An update on the aspects of Zika virus infection on male reproductive system

Borges

Vireque

Berteli

et al. 2019

J Assist Reprod Genet

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Zika virus (ZIKV) is mainly transmitted through Aedes mosquito bites, but sexual and post-transfusion transmissions have been reported. During acute infection, ZIKV is detectable in most organs and body fluids including human semen. Although it is not currently epidemic, there is a concern that the virus can still reemerge since the male genital tract might harbor persistent reservoirs that could facilitate viral transmission over extended periods, raising concerns among public health and assisted reproductive technologies (ART) experts and professionals. So far, the consensus is that ZIKV infection in the testes or epididymis might affect sperm development and, consequently, male fertility. Still, diagnostic tests have not yet been adapted to resource-restricted countries. This manuscript provides an updated overview of the cellular and molecular mechanisms of ZIKV infection and reviews data on ZIKV persistence in semen and associated risks to the male reproductive system described in human and animal models studies. We provide an updated summary of the impact of the recent ZIKVoutbreak on human-ART, weighing on current recommendations and diagnostic approaches, both available and prospective, with special emphasis on mass spectrometry-based biomarker discovery. In the light of the identified gaps in our accumulated knowledge on the subject, we highlight the importance for couples seeking ART to follow the constantly revised guidelines and the need of specific ZIKV diagnosis tools for semen screening to contain ZIKV virus spread and make ART safer.

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Zika Virus Trafficking and Interactions in the Human Male Reproductive Tract

Cited by 7 publications

References 122 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

Immune outcomes of Zika virus infection in nonhuman primates

An update on the aspects of Zika virus infection on male reproductive system

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