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A Mouse Model of Zika Virus Sexual Transmission and Vaginal Viral Replication.

ABSTRACT: Case reports of Zika virus (ZIKV) sexual transmission and genital persistence are mounting. Venereal transmission and genital persistence threaten public health within and beyond the range of ZIKV's mosquito vectors. In this study, we administered ZIKV into the vaginas of AG129 mice and LysMCre+IFNARfl/fl C57BL/6 mice after hormonal treatments. Mice infected during estrus-like phase were resistant to vaginal infection. In contrast, when infected during diestrus-like phase, AG129 mice succumbed to infection, whereas LysMCre+IFNARfl/fl mice experienced transient illness. Patency of transgenital transmission (TGT) in diestrus-like mice was demonstrated by detection of viremia and ZIKV replication in spleen and brain, and viral RNA persisted in vaginal washes as late as 10 days post-infection. In these lethal and sublethal mouse models, this study indicates that intravaginal deposition of ZIKV can cause TGT, hormonal changes in the female reproductive tract (FRT) influence transmission, and ZIKV replication persists in the FRT for several days.

SUBMITTER: Tang WW

PROVIDER: S-EPMC5193244 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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A Mouse Model of Zika Virus Sexual Transmission and Vaginal Viral Replication.

Tang William Weihao WW Young Matthew Perry MP Mamidi Anila A Regla-Nava Jose Angel JA Kim Kenneth K Shresta Sujan S

Cell reports 20161201 12

Case reports of Zika virus (ZIKV) sexual transmission and genital persistence are mounting. Venereal transmission and genital persistence threaten public health within and beyond the range of ZIKV's mosquito vectors. In this study, we administered ZIKV into the vaginas of AG129 mice and LysMCre<sup>+</sup>IFNAR<sup>fl/fl</sup> C57BL/6 mice after hormonal treatments. Mice infected during estrus-like phase were resistant to vaginal infection. In contrast, when infected during diestrus-like phase, ...[more]

PMID: 28009279

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Project description:Zika virus (ZIKV) can establish infection in immune privileged sites such as the testes, eye, and placenta. Whether ZIKV infection of white blood cells is required for dissemination of the virus to immune privileged sites has not been definitively shown. To assess whether initial ZIKV replication in myeloid cell populations is critical for dissemination during acute infection, recombinant ZIKVs were generated that could not replicate in these specific cells. ZIKV was cell restricted by insertion of a complementary sequence to a myeloid-specific microRNA in the 3' untranslated region. Following inoculation of a highly sensitive immunodeficient mouse model, crucial immune parameters, such as quantification of leukocyte cell subsets, cytokine and chemokine secretion, and viremia, were assessed. Decreased neutrophil numbers in the spleen were observed during acute infection with myeloid-restricted ZIKV that precluded the generation of viremia and viral dissemination to peripheral organs. Mice inoculated with a nontarget microRNA control ZIKV demonstrated increased expression of key cytokines and chemokines critical for neutrophil and monocyte recruitment and increased neutrophil influx in the spleen. In addition, ZIKV-infected Ly6Chi monocytes were identified in vivo in the spleen. Mice inoculated with myeloid-restricted ZIKV had a decrease in Ly6Chi ZIKV RNA-positive monocytes and a lack of inflammatory cytokine production compared to mice inoculated with control ZIKV.IMPORTANCE Myeloid cells, including monocytes, play a crucial role in immune responses to pathogens. Monocytes have also been implicated as "Trojan horses" during viral infections, carrying infectious virus particles to immune privileged sites and/or to sites protected by physical blood-tissue barriers, such as the blood-testis barrier and the blood-brain barrier. In this study, we found that myeloid cells are crucial to Zika virus (ZIKV) pathogenesis. By engineering ZIKV clones to encode myeloid-specific microRNA target sequences, viral replication was inhibited in myeloid cells by harnessing the RNA interference pathway. Severely immunodeficient mice inoculated with myeloid-restricted ZIKV did not demonstrate clinical signs of disease and survived infection. Furthermore, viral dissemination to peripheral organs was not observed in these mice. Lastly, we identified Ly6Cmid/hi murine monocytes as the major myeloid cell population that disseminates ZIKV.

Project description:The human vaginal microbiome (VMB) is a complex bacterial community that interacts closely with vaginal epithelial cells (VECs) impacting the mucosal phenotype and its responses to pathogenic insults. The VMB and VEC relationship includes nutrient exchange and regulation of signaling molecules that controls numerous host functions and defends against invading pathogens. To better understand infection and replication of sexually transmitted viral pathogens in the human vaginal mucosa we used our ex vivo VEC multilayer culture system. We tested the hypothesis that selected VMB communities could be identified that alter the replication of sexually transmitted viruses consistent with reported clinical associations. Sterile VEC multilayer cultures or those colonized with VMB dominated by specific Lactobacillus spp., or VMB lacking lactobacilli, were infected with Zika virus, (ZIKV) a single stranded RNA virus, or Herpes Simplex Virus type 2 (HSV-2), a double stranded DNA virus. The virus was added to the apical surface of the cultured VEC multilayer to model transmission during vaginal intercourse. Viral replication was measured 48 h later by qPCR. The results indicated that VEC cultures colonized by VMB containing Staphylococcus spp., previously reported as inflammatory, significantly reduced the quantity of viral genomes produced by ZIKV. HSV-2 titers were decreased by nearly every VMB tested relative to the sterile control, although Lactobacillus spp.-dominated VMBs caused the greatest reduction in HSV-2 titer consistent with clinical observations. To explore the mechanism for reduced ZIKV titers, we investigated inflammation created by ZIKV infection, VMB colonization or pre-exposure to selected TLR agonists. Finally, expression levels of human beta defensins 1-3 were quantified in cultures infected by ZIKV and those colonized by VMBs that impacted ZIKV titers. Human beta defensins 1-3 produced by the VEC showed no association with ZIKV titers. The data presented expands the utility of this ex vivo model system providing controlled and reproducible methods to study the VMB impact on STIs and indicated an association between viral replication and specific bacterial species within the VMB.

Project description:BackgroundHealth authorities in the United States and Europe reported an increasing number of travel-associated episodes of sexual transmission of Zika virus (ZIKV) following the 2015-2017 ZIKV outbreak. This, and other scientific evidence, suggests that ZIKV is sexually transmissible in addition to having its primary mosquito-borne route. The objective of this systematic review and evidence synthesis was to clarify the epidemiology of sexually transmitted ZIKV.Methods and findingsWe performed a living (i.e., continually updated) systematic review of evidence published up to 15 April 2018 about sexual transmission of ZIKV and other arthropod-borne flaviviruses in humans and other animals. We defined 7 key elements of ZIKV sexual transmission for which we extracted data: (1) rectal and vaginal susceptibility to infection, (2) incubation period following sexual transmission, (3) serial interval between the onset of symptoms in a primary and secondary infected individuals, (4) duration of infectiousness, (5) reproduction number, (6) probability of transmission per sex act, and (7) transmission rate. We identified 1,227 unique publications and included 128, of which 77 presented data on humans and 51 presented data on animals. Laboratory experiments confirm that rectal and vaginal mucosae are susceptible to infection with ZIKV and that the testis serves as a reservoir for the virus in animal models. Sexual transmission was reported in 36 human couples: 34/36 of these involved male-to-female sexual transmission. The median serial symptom onset interval in 15 couples was 12 days (interquartile range: 10-14.5); the maximum was 44 days. We found evidence from 2 prospective cohorts that ZIKV RNA is present in human semen with a median duration of 34 days (95% CI: 28-41 days) and 35 days (no CI given) (low certainty of evidence, according to GRADE). Aggregated data about detection of ZIKV RNA from 37 case reports and case series indicate a median duration of detection of ZIKV of 40 days (95% CI: 30-49 days) and maximum duration of 370 days in semen. In human vaginal fluid, median duration was 14 days (95% CI: 7-20 days) and maximum duration was 37 days (very low certainty). Infectious virus in human semen was detected for a median duration of 12 days (95% CI: 1-21 days) and maximum of 69 days. Modelling studies indicate that the reproduction number is below 1 (very low certainty). Evidence was lacking to estimate the incubation period or the transmission rate. Evidence on sexual transmission of other flaviviruses was scarce. The certainty of the evidence is limited because of uncontrolled residual bias.ConclusionsThe living systematic review and sexual transmission framework allowed us to assess evidence about the risk of sexual transmission of ZIKV. ZIKV is more likely transmitted from men to women than from women to men. For other flaviviruses, evidence of sexual transmissibility is still absent. Taking into account all available data about the duration of detection of ZIKV in culture and from the serial interval, our findings suggest that the infectious period for sexual transmission of ZIKV is shorter than estimates from the earliest post-outbreak studies, which were based on reverse transcription PCR alone.

Project description:Zika virus (ZIKV) is an arboviral infection that has been shown to be sexually transmitted. The study outlined herein aims to determine if accessory sex glands and epididymal epithelial cells are sources of viral persistence in subacute and chronic ZIKV infection, and if infection of these organs is important in sexual transmission during long-term (chronic) infection. Male interferon type I receptor knockout (Ifnar-/-) mice were challenged with ZIKV and reproductive tissues were harvested 14 and 35 days post infection (DPI) for inoculation studies and 14, 35 and 70 DPI for histopathology. Artificial insemination fluid derived from epididymal flush and seminal plasma from the prostate and seminal vesicle was obtained from ZIKV inoculated and sham-infected males. Naïve interferon type I and II receptor knockout (AG129) female mice were pre-treated with progesterone and inoculated intravaginally with artificial insemination fluid from ZIKV-infected males. ZIKV RNA was detected in the artificial insemination fluid generated from epididymal flush or seminal plasma from ZIKV infected males at 14 and 35 DPI. ZIKV antigens were only detected in seminiferous tubules at 14 DPI. Epididymal epithelial cells did not show ZIKV antigen immunoreactivity at 14, 35 or 70 DPI. Severe fibrosing orchitis (end stage orchitis) was observed at 35 and 70 DPI. Mild inflammation and peri-tubular fibrosis were observed in the epididymis following clearance of virus. Viral RNA was not detected by PCR in whole blood samples of females from any intravaginal experimental group and only detected in 20% of subcutaneously inoculated animals (derived from 1 experimentally infected male) at 35 DPI. While ZIKV RNA and antigens can be detected in the male reproductive tract at 14 DPI and RNA can also be detected at 35 DPI, intravaginal inoculation of artificial insemination fluid from these time-points failed to result in viremia in naïve females inoculated intravaginally. These studies support the hypothesis that epididymal epithelial cells are critical to sexual transmission in immunocompromised mice. Additionally, acute but not chronic male reproductive tract infection with ZIKV results in infectious virus capable of being sexually transmitted in mice.

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A Mouse Model of Zika Virus Sexual Transmission and Vaginal Viral Replication.

Publications

A Mouse Model of Zika Virus Sexual Transmission and Vaginal Viral Replication.

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