Zika virus (ZIKV) infection of pregnant women can cause congenital malformations including microcephaly, which has focused global attention on this emerging pathogen1. In addition to transmission by mosquitoes, ZIKV can be detected in the seminal fluid of affected males for extended periods of time and transmitted sexually2. Here, using a mouse-adapted African ZIKV strain (Dakar 41519) we evaluated the consequences of infection in the male reproductive tract of mice. We observed persistence of ZIKV, but not the closely related Dengue virus (DENV), in the testis and epididymis of male mice, and this was associated with tissue injury that caused diminished testosterone and inhibin B levels, and oligospermia. ZIKV preferentially infected spermatogonia, primary spermatocytes, and Sertoli cells in the testis, resulting in cell death and destruction of the seminiferous tubules. Less damage was observed with a contemporary Asian ZIKV strain (H/PF/2013), in part because this virus replicates less efficiently in mice. The extent to which these observations in mice translate to humans remains unclear, but longitudinal studies of sperm function and viability in ZIKV-infected humans seem warranted.

The Zika virus (ZIKV) epidemic has resulted in congenital abnormalities in fetuses and neonates. Although some cross-reactive DENV antibodies can enhance ZIKV infection in mice, those recognizing the E-dimer epitope (EDE) can neutralize ZIKV infection in cell culture. We evaluated the therapeutic activity of human EDE monoclonal antibodies (mAbs) for their ability to control ZIKV infection in the brains, testes, placentas, and fetuses of mice. A single dose of EDE1-B10 antibody given three days after infection protected against lethality, reduced ZIKV levels in brains and testes, and preserved sperm counts. In pregnant mice, wild-type or engineered LALA variants of EDE1-B10, which cannot engage Fc-γ receptors, diminished ZIKV burden in maternal and fetal tissues, and protected against fetal demise. As neutralizing EDE antibodies, in addition to their established inhibitory effects against DENV, have therapeutic potential against ZIKV, it may be possible to develop therapies that control disease caused by both viruses.

The aryl hydrocarbon receptor (AHR) is known for its roles in xenobiotic metabolism and essential physiologic processes such as cell growth, death, and differentiation. AHR is also an important regulator of male reproductive processes. However, no studies have characterized the consequences of loss of AHR in spermatogenesis. We used Ahr knockout (Ahr(-/-)) mice to assess the effects of loss of AHR on the architecture and gene expression of the seminiferous epithelium and functional sperm outcomes. The histopathological defects of the Ahr(-/-)seminiferous epithelium included vacuoles, multinucleated giant cells, hypocellularity with widened intercellular spaces, apical sloughing, and an excess number of retained elongated spermatids. Quantitative real-time PCR revealed significant down-regulation of Testin and Magea4, indicating Sertoli cell and spermatogenic dysregulation. Moreover, the reduced expression of Hspa2, Prm1, and Prm2 as well as decreased expression of Nrf2, Sod2, and Ucp2 suggested poorly remodeled germ cells with increased vulnerability to oxidative stress. In wild-type sperm, AHR protein was localized to the acrosome and the principal piece of the mature sperm flagellum. The in vitro fertilization rate was significantly lower with Ahr(-/-) sperm as compared to wild-type sperm, and there were morphologic abnormalities of the Ahr(-/-) sperm head and tail. Taken together, our data indicate that AHR plays an important role in normal sperm development.

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