Abstract
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.
Highlights
Humans[9,10,11,12,13]
Zika virus (ZIKV) antigens were only detected in the testicle at 14 days post infection (DPI), coinciding with the severe, necrotizing orchitis (Fig. 1F)
We have shown that epididymal epithelial cells are a likely source of infectious virions during the acute phase of male reproductive tract disease, and accessory sex glands (ASG) may serve as a source of infectious virus[8]
Summary
Humans[9,10,11,12,13]. Though the virus is primarily transmitted through Aedes mosquitoes vectors[14,15], sexual transmission of ZIKV may attribute to low-level transmission in regions that are not endemic to suitable arthropod vectors. We have shown that artificial insemination fluid derived from either seminal plasma (prostatic and seminal vesicular homogenates) or epididymal flush from a ZIKV infected male mouse is capable of resulting in peripheral viremia in artificially inseminated, naïve, immunocompromised female mice[8]. These data support the hypothesis that epithelial cells of the reproductive tract support active viral replication with production of infectious virions during acute ZIKV infection. We show that while the testicle develops a severe, irreparable, granulomatous orchitis, the epididymis and ASGs of Ifnar−/− mice are capable of resolving ZIKV infection associated lesions in the chronic stages of disease without severe histopathologic sequelae
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