Zika virus infects human Sertoli cells and trespass the blood-testes barrier to migrate across the seminiferous epithelium

Abstract

Abstract The 2015–2016 epidemic of Zika virus (ZIKV) has identified sexual transmission as a new route of disease spread. Presence of ZIKV in the semen when viremia is undetectable in humans suggests the ability of ZIKV to establish infection in the testes. Lack of specific therapeutic drugs to clear testicular infection warrants understanding of the associated mechanisms. Seminiferous tubules, the site of spermatogenesis, is an immune privileged site with an effective blood-testes barrier (BTB) constituted exclusively by specialized tight junctions proteins (TJP) between the adjacent Sertoli cells (SC) that protects germ cells from systemic immune attack. Increased inflammatory mediators such as TNF-α, IL-1β, matrix metalloproteinases and cell-adhesion molecules (CAMs) can disrupt BTB and facilitate testicular infections. We determined the infection kinetics of ZIKV in SC and its association with antiviral defense and BTB integrity. We demonstrate that SC were susceptible to ZIKV and induced cytokines (IFN-α, IFN-γ, TNF-α) and CAMs (VCAM), which correlated with peak virus titers. Interestingly, while ZIKV transmigrated efficiently across the in vitro BTB model, it did not affect barrier integrity, also supported by no difference observed in the levels of TJP such as ZO-1 and claudin between control and infected SC. However, the integrity of the BTB model decreased significantly following exposure to the supernatant from ZIKV-infected macrophages. Collectively, our data suggests infection of SC as one of the routes of virus transmigration into the seminiferous tubules and that inflammatory mediators from infected human macrophages may further compromise integrity of BTB thereby allowing persistent infection of ZIKV in the testes.