Abstract
Zika virus is a teratogenic mosquito-transmitted flavivirus that is associated with birth defects in newborns and Guillain–Barré syndrome in adults. The virus can also be sexually transmitted, but currently, very little is known about the cell types supporting virus replication and persistence in human testes. Using primary cell cultures, we observed that Sertoli but not Leydig cells are highly susceptible to Zika virus infection, a process that is dependent on the TAM family receptor Axl. In cell culture, Sertoli cells could be productively infected with Zika virus for at least 6-weeks. Infection of Sertoli cells resulted in dramatic changes to the transcriptional profile of these cells. The most upregulated mRNA in infected cells was basic fibroblast growth factor (FGF2), a cytokine that was found to enhance Zika virus replication and support viral persistence. Together these findings provide key insights into understanding how Zika virus persists in the male reproductive tract and in turn may aid in developing antiviral therapies or strategies to minimize sexual transmission of this pathogen.
Highlights
Zika virus (ZIKV) is a major arboviral pathogen responsible for a recent pandemic outbreak in South and Central America[1]
Because Sertoli cells were much more permissive to ZIKV than Leydig cells, the rest of our studies focused on ZIKV replication in the former cell type
This mode of infection not the major route of transmission in endemic areas, infected males who return from endemic regions pose a significant risk to their partners who reside outside areas where ZIKV is circulating
Summary
Zika virus (ZIKV) is a major arboviral pathogen responsible for a recent pandemic outbreak in South and Central America[1]. As well as vector-based transmission, ZIKV infection can occur through sexual contact[3,4,5]. This phenomenon has been recapitulated in both mouse[6,7,8] and macaque models[9,10]. Sertoli cells form the testis-blood barrier, which is critical for protecting the male reproductive tract from pathogens[14] Leydig cells are another important cell type in testes that produce and secrete the male sex hormone testosterone and are required for development of male reproductive tissue and secondary sexual characteristics[15]. We show that ZIKV replication in Sertoli cells can be significantly inhibited by a number of drugs including an FGF receptor antagonist indicating potential therapeutic options to limit sexual transmission
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