Abstract
Recognition of Zika virus (ZIKV) sexual transmission (ST) among humans challenges our understanding of the maintenance of mosquito-borne viruses in nature. Here we dissected the relative contributions of the components of male reproductive system (MRS) during early male-to-female ZIKV transmission by utilizing mice with altered antiviral responses, in which ZIKV is provided an equal opportunity to be seeded in the MRS tissues. Using microRNA-targeted ZIKV clones engineered to abolish viral infectivity to different parts of the MRS or a library of ZIKV genomes with unique molecular identifiers, we pinpoint epithelial cells of the epididymis (rather than cells of the testis, vas deferens, prostate, or seminal vesicles) as a most likely source of the sexually transmitted ZIKV genomes during the early (most productive) phase of ZIKV shedding into the semen. Incorporation of this mechanistic knowledge into the development of a live-attenuated ZIKV vaccine restricts its ST potential.
Highlights
Recognition of Zika virus (ZIKV) sexual transmission (ST) among humans challenges our understanding of the maintenance of mosquito-borne viruses in nature
All components of the male reproductive system (MRS) may be seeded by ZIKV from the blood, support virus replication, and contribute to the viral shedding into the final product of the MRS—the ejaculate
We previously reported the construction of a liveattenuated ZIKV vaccine candidate virus C/3′NCR-mir(T) that contains multiple miRNA targets (Fig. 7a), including two targets for the testicular mir-202 miRNA, two targets for the epithelial mir-141miRNA, and targets for mir-9 and mir-124 miRNAs that are highly expressed in the central nervous system (CNS)
Summary
Recognition of Zika virus (ZIKV) sexual transmission (ST) among humans challenges our understanding of the maintenance of mosquito-borne viruses in nature. Using microRNAtargeted ZIKV clones engineered to abolish viral infectivity to different parts of the MRS or a library of ZIKV genomes with unique molecular identifiers, we pinpoint epithelial cells of the epididymis (rather than cells of the testis, vas deferens, prostate, or seminal vesicles) as a most likely source of the sexually transmitted ZIKV genomes during the early (most productive) phase of ZIKV shedding into the semen. Incorporation of this mechanistic knowledge into the development of a live-attenuated ZIKV vaccine restricts its ST potential. We used two independent yet complementary strategies that allowed us (i) to block ZIKV replication in various parts of the MRS by microRNA(miRNA)-targeting of viral genome and (ii) to trace the MRS tissue-dependent ZIKV progenies by the unique molecular identifiers (barcodes) incorporated into viral genome
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