Abstract
Sexual transmission and persistence of Zika virus (ZIKV) in the male reproductive tract (MRT) poses new challenges for controlling virus outbreaks and developing live-attenuated vaccines. To elucidate routes of ZIKV dissemination in the MRT, we here generate microRNA-targeted ZIKV clones that lose the infectivity for (1) the cells inside seminiferous tubules of the testis, or (2) epithelial cells of the epididymis. We trace ZIKV dissemination in the MRT using an established mouse model of ZIKV pathogenesis. Our results support a model in which ZIKV infects the testis via a hematogenous route, while infection of the epididymis can occur via two routes: (1) hematogenous/lymphogenous and (2) excurrent testicular. Co-targeting of the ZIKV genome with brain-, testis-, and epididymis-specific microRNAs restricts virus infection of these organs, but does not affect virus-induced protective immunity in mice and monkeys. These defined alterations of ZIKV tropism represent a rational design of a safe live-attenuated ZIKV vaccine.
Highlights
Sexual transmission and persistence of Zika virus (ZIKV) in the male reproductive tract (MRT) poses new challenges for controlling virus outbreaks and developing live-attenuated vaccines
We focused on the two time points (3 and 12 dpi) for future evaluation of infection with all miRNA-targeted ZIKV clones
Sequencing analysis of the 2×scr virus that was isolated from the spleen (3 dpi; n = 3), brain (12 dpi; n = 7), testis (12 dpi; n = 7), and epididymis (12 dpi; n = 4) showed that the inserted sequences remained intact
Summary
Sexual transmission and persistence of Zika virus (ZIKV) in the male reproductive tract (MRT) poses new challenges for controlling virus outbreaks and developing live-attenuated vaccines. Co-targeting of the ZIKV genome with brain-, testis-, and epididymis-specific microRNAs restricts virus infection of these organs, but does not affect virus-induced protective immunity in mice and monkeys. These defined alterations of ZIKV tropism represent a rational design of a safe live-attenuated ZIKV vaccine. ZIKV is capable of establishing long-term persistent infection in humans and utilizing non-vector transmission routes. The long-term viral persistence in male reproductive tract (MRT) and the newly described route of transmission pose new challenges for controlling ZIKV outbreaks and for the development of a safe live-attenuated ZIKV vaccine. As ZIKV generated in one part of the MRT can be transported to the other parts located downstream of excurrent flow, we focus only on the ZIKV interaction with major upstream organs, namely, the testis and epididymis
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