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

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1006 ◽  
Author(s):  
Raquel das Neves Almeida ◽  
Heloisa Antoniella Braz-de-Melo ◽  
Igor de Oliveira Santos ◽  
Rafael Corrêa ◽  
Gary P. Kobinger ◽  
...  
Keyword(s):  
Germ Cells ◽  
Zika Virus ◽  
Male Fertility ◽  
Cellular Response ◽  
Reproductive Tract ◽  
Human Reproduction ◽  
Testicular Atrophy ◽  
Zikv Infection ◽  
Male Reproductive Tract ◽  
Current Vaccine

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.

scholarly journals Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Thomas E. Morrison ◽  
Michael S. Diamond
Keyword(s):  
Animal Models ◽  
Virus Infection ◽  
Zika Virus ◽  
Congenital Malformations ◽  
Scientific Community ◽  
Reproductive Tract ◽  
Sexual Transmission ◽  
Rapid Testing ◽  
Zikv Infection ◽  
Male Reproductive Tract

ABSTRACT Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that now causes epidemics affecting millions of people on multiple continents. The virus has received global attention because of some of its unusual epidemiological and clinical features, including persistent infection in the male reproductive tract and sexual transmission, an ability to cross the placenta during pregnancy and infect the developing fetus to cause congenital malformations, and its association with Guillain-Barré syndrome in adults. This past year has witnessed an intensive effort by the global scientific community to understand the biology of ZIKV and to develop pathogenesis models for the rapid testing of possible countermeasures. Here, we review the recent advances in and utility and limitations of newly developed mouse and nonhuman primate models of ZIKV infection and pathogenesis.

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

Viruses ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 291
Author(s):  
Erika R. Schwarz ◽  
Lilian J. Oliveira ◽  
Francesco Bonfante ◽  
Ruiyu Pu ◽  
Malgorzata A. Pozor ◽  
...  
Keyword(s):  
Zika Virus ◽  
Post Infection ◽  
Reproductive Tract ◽  
Sexual Transmission ◽  
Infection Model ◽  
Intact Male ◽  
Zikv Infection ◽  
Male Reproductive Tract ◽  
Pregnant Sheep ◽  
Male Sheep

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).

scholarly journals Persistence of Zika virus RNA in the epididymis of the male reproductive tract

2020 ◽  
Author(s):  
Megan B. Vogt ◽  
Francesca Frere ◽  
Seth A. Hawks ◽  
Claudia E. Perez ◽  
Sheryl Coutermarsh-Ott ◽  
...  
Keyword(s):  
Birth Defects ◽  
Persistent Infection ◽  
Zika Virus ◽  
Reproductive Tract ◽  
Infectious Virus ◽  
Sexual Transmission ◽  
In Utero ◽  
Zikv Infection ◽  
Male Reproductive Tract ◽  
Health Decisions

ABSTRACTZika virus (ZIKV) can infect developing fetuses in utero and cause severe congenital defects. This in utero transmission can occurs following ZIKV infection during pregnancy via sexual transmission or mosquito bite. Infected men may shed ZIKV RNA in semen for over six months post symptom onset, indicating that ZIKV may persistently infect the male reproductive tract (MRT). However, the site of persistent infection in the MRT and whether ZIKV can recrudesce in the MRT is unknown. We hypothesized that if ZIKV establishes a persistent infection in the MRT, then immunosuppressant treatment should stimulate ZIKV replication. We tested this hypothesis in a wild-type mouse model of ZIKV sexual transmission. Male mice were infected with ZIKV and immunosuppressed when they no longer shed infectious virus in their ejaculates. After immunosuppression, ejaculates and MRT tissues were monitored for infectious virus and ZIKV RNA. Our results show that ZIKV recrudescence did not occur following immunosuppression, as we did not detect significant levels of infectious virus in ejaculates or MRT tissues following immunosuppression. We did detect ZIKV RNA in the epididymides of mice treated with the immunosuppressant cyclophosphamide. Further analysis revealed that this ZIKV RNA was contained within the lumen of the epididymis. Our findings suggest that ZIKV persistently infects the epididymis within the male reproductive tract. This study provides insight into the mechanisms behind ZIKV sexual transmission, which may inform public health decisions regarding ZIKV risks.ImportanceZika virus (ZIKV) is an emerging mosquito-transmitted virus that typically causes mild and self-limiting febrile illness in humans; however, during the recent epidemic of ZIKV in the Americas, severe birth defects, such as microcephaly and club foot, were reported in infants born to ZIKV infected mothers. Additionally, sexual transmission has been identified as a secondary method of ZIKV transmission. Since ZIKV can be isolated from semen of infected men long after initial infection, it is imperative to understand the mechanism(s) of ZIKV infection of the male reproductive tract to prevent sexual transmission and ZIKV-associated birth defects. The significance of our research is in identifying a site of persistent ZIKV infection in the male reproductive tract and in assessing the likelihood that a persistently infected individual will begin shedding infectious virus in semen again. This information will enhance our understanding of ZIKV sexual transmission and inform health decisions regarding ZIKV risks.

scholarly journals Identification of multiple male reproductive tract-specific proteins that regulate sperm migration through the oviduct in mice

2019 ◽  
Vol 116 (37) ◽  
pp. 18498-18506 ◽  
Author(s):  
Yoshitaka Fujihara ◽  
Taichi Noda ◽  
Kiyonori Kobayashi ◽  
Asami Oji ◽  
Sumire Kobayashi ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Male Fertility ◽  
Reproductive Tract ◽  
Gene Families ◽  
Gene Clusters ◽  
Mutant Mice ◽  
Male Reproductive Tract ◽  
Sperm Migration ◽  
Specific Proteins ◽  
Multiple Male

CRISPR/Cas9-mediated genome editing technology enables researchers to efficiently generate and analyze genetically modified animals. We have taken advantage of this game-changing technology to uncover essential factors for fertility. In this study, we generated knockouts (KOs) of multiple male reproductive organ-specific genes and performed phenotypic screening of these null mutant mice to attempt to identify proteins essential for male fertility. We focused on making large deletions (dels) within 2 gene clusters encoding cystatin (CST) and prostate and testis expressed (PATE) proteins and individual gene mutations in 2 other gene families encoding glycerophosphodiester phosphodiesterase domain (GDPD) containing and lymphocyte antigen 6 (Ly6)/Plaur domain (LYPD) containing proteins. These gene families were chosen because many of the genes demonstrate male reproductive tract-specific expression. AlthoughGdpd1andGdpd4mutant mice were fertile, disruptions ofCstandPategene clusters andLypd4resulted in male sterility or severe fertility defects secondary to impaired sperm migration through the oviduct. While absence of the epididymal protein families CST and PATE affect the localization of the sperm membrane protein A disintegrin and metallopeptidase domain 3 (ADAM3), the sperm acrosomal membrane protein LYPD4 regulates sperm fertilizing ability via an ADAM3-independent pathway. Thus, use of CRISPR/Cas9 technologies has allowed us to quickly rule in and rule out proteins required for male fertility and expand our list of male-specific proteins that function in sperm migration through the oviduct.

scholarly journals From Mosquito Bites to Sexual Transmission: Evaluating Mouse Models of Zika Virus Infection

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2244
Author(s):  
Elizabeth Balint ◽  
Amelia Montemarano ◽  
Emily Feng ◽  
Ali A. Ashkar
Keyword(s):  
Mouse Models ◽  
Zika Virus ◽  
Reproductive Tract ◽  
Sexual Transmission ◽  
Zikv Infection ◽  
Sexually Transmitted ◽  
Advantages And Disadvantages ◽  
Effective Use ◽  
The Impact ◽  
Male To Female

Following the recent outbreak of Zika virus (ZIKV) infections in Latin America, ZIKV has emerged as a global health threat due to its ability to induce neurological disease in both adults and the developing fetus. ZIKV is largely mosquito-borne and is now endemic in many parts of Africa, Asia, and South America. However, several reports have demonstrated persistent ZIKV infection of the male reproductive tract and evidence of male-to-female sexual transmission of ZIKV. Sexual transmission may broaden the reach of ZIKV infections beyond its current geographical limits, presenting a significant threat worldwide. Several mouse models of ZIKV infection have been developed to investigate ZIKV pathogenesis and develop effective vaccines and therapeutics. However, the majority of these models focus on mosquito-borne infection, while few have considered the impact of sexual transmission on immunity and pathogenesis. This review will examine the advantages and disadvantages of current models of mosquito-borne and sexually transmitted ZIKV and provide recommendations for the effective use of ZIKV mouse models.

scholarly journals Zika virus in rhesus macaque semen and reproductive tract tissues: a pilot study of acute infection†

2020 ◽  
Vol 103 (5) ◽  
pp. 1030-1042 ◽  
Author(s):  
Jenna K Schmidt ◽  
Katherine D Mean ◽  
Riley C Puntney ◽  
Eric S Alexander ◽  
Ruth Sullivan ◽  
...  
Keyword(s):  
Pilot Study ◽  
Rhesus Macaque ◽  
Zika Virus ◽  
Reproductive Tract ◽  
Acute Infection ◽  
Viral Rna ◽  
Viral Reservoir ◽  
Computer Assisted ◽  
Male Reproductive Tract ◽  
The Impact

Abstract Although sexual transmission of Zika virus (ZIKV) is well-documented, the viral reservoir(s) in the male reproductive tract remains uncertain in humans and immune-intact animal models. We evaluated the presence of ZIKV in a rhesus macaque pilot study to determine persistence in semen, assess the impact of infection on sperm functional characteristics, and define the viral reservoir in the male reproductive tract. Five adult male rhesus monkeys were inoculated with 105 PFU of Asian-lineage ZIKV isolate PRVABC59, and two males were inoculated with the same dose of African-lineage ZIKV DAKAR41524. Viremia and viral RNA (vRNA) shedding in semen were monitored, and a cohort of animals were necropsied for tissue collection to assess tissue vRNA burden and histopathology. All animals exhibited viremia for limited periods (1–11 days); duration of shedding did not differ significantly between viral isolates. There were sporadic low levels of vRNA in the semen from some, but not all animals. Viral RNA levels in reproductive tract tissues were also modest and present in the epididymis in three of five cases, one case in the vas deferens, but not detected in testis, seminal vesicles or prostate. ZIKV infection did not impact semen motility parameters as assessed by computer-assisted sperm analysis. Despite some evidence of prolonged ZIKV RNA shedding in human semen and high tropism of ZIKV for male reproductive tract tissues in mice deficient in Type 1 interferon signaling, in the rhesus macaques assessed in this pilot study, we did not consistently find ZIKV RNA in the male reproductive tract.

scholarly journals Animal Models of Zika Virus Infection during Pregnancy

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 598 ◽  
Author(s):  
Elizabeth Caine ◽  
Brett Jagger ◽  
Michael Diamond
Keyword(s):  
Animal Models ◽  
Virus Infection ◽  
Zika Virus ◽  
Reproductive Tract ◽  
Congenital Abnormalities ◽  
Tissue Tropism ◽  
Zikv Infection ◽  
In Vivo Models ◽  
Sexually Transmitted

Zika virus (ZIKV) emerged suddenly in the Americas in 2015 and was associated with a widespread outbreak of microcephaly and other severe congenital abnormalities in infants born to mothers infected during pregnancy. Vertical transmission of ZIKV in humans was confirmed when viral RNA was detected in fetal and placental tissues, and this outcome has been recapitulated experimentally in animals. Unlike other flaviviruses, ZIKV is both arthropod- and sexually-transmitted, and has a broad tissue tropism in humans, including multiple tissues of the reproductive tract. The threats posed by ZIKV have prompted the development of multiple in vivo models to better understand the pathogenesis of ZIKV, particularly during pregnancy. Here, we review the progress on animal models of ZIKV infection during pregnancy. These studies have generated a foundation of insights into the biology of ZIKV, and provide a means for evaluating vaccines and therapeutics.

scholarly journals Zika Virus Trafficking and Interactions in the Human Male Reproductive Tract

Pathogens ◽  
2018 ◽  
Vol 7 (2) ◽  
pp. 51 ◽  
Author(s):  
Lucia Da Silva
Keyword(s):  
Zika Virus ◽  
Reproductive Tract ◽  
Sexual Transmission ◽  
Host Cells ◽  
Future Research ◽  
Mosquito Vector ◽  
Male Reproductive Tract ◽  
Unprotected Sexual Intercourse ◽  
Human Male ◽  
Viral Interactions

Sexual transmission of Zika virus (ZIKV) is a matter of great concern. Infectious viral particles can be shed in semen for as long as six months after infection and can be transferred to male and female sexual partners during unprotected sexual intercourse. The virus can be found inside spermatozoa and could be directly transferred to the oocyte during fertilization. Sexual transmission of ZIKV can contribute to the rise in number of infected individuals in endemic areas as well as in countries where the mosquito vector does not thrive. There is also the possibility, as has been demonstrated in mouse models, that the vaginal deposition of ZIKV particles present in semen could lead to congenital syndrome. In this paper, we review the current literature to understand ZIKV trafficking from the bloodstream to the human male reproductive tract and viral interactions with host cells in interstitial spaces, tubule walls, annexed glands and semen. We hope to highlight gaps to be filled by future research and potential routes for vaccine and antiviral development.

scholarly journals Trimester-specific Zika virus infection affects placental responses in women

2019 ◽  
Author(s):  
Fok-Moon Lum ◽  
Vipin Narang ◽  
Susan Hue ◽  
Jie Chen ◽  
Naomi McGovern ◽  
...  
Keyword(s):  
Birth Defects ◽  
Zika Virus ◽  
Cellular Response ◽  
Prenatal Screening ◽  
Acute Infection ◽  
Transcriptomic Analysis ◽  
Placental Development ◽  
Zikv Infection ◽  
Hofbauer Cells ◽  
Screening Procedures

AbstractZika virus (ZIKV) infection during pregnancy is associated with neurologic birth defects, but the effects on placental development are unclear. Full-term placentas from three women, each infected with ZIKV during specific pregnancy trimesters, were harvested for anatomic, immunologic and transcriptomic analysis. In this study, each woman exhibited a unique immune response, but they collectively diverged from healthy controls with raised IL-1RA, IP-10, EGF and RANTES expression, and neutrophil numbers during the acute infection phase. Although ZIKV NS3 antigens co-localized to placental Hofbauer cells, the placentas showed no anatomical defects. Transcriptomic analysis of samples from the placentas revealed that infection during trimester 1 caused a disparate cellular response centered on differential eIF2 signaling, mitochondrial dysfunction and oxidative phosphorylation. These findings should translate to improve clinical prenatal screening procedures for virus-infected pregnant patients.

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