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The testis is a reservoir for viruses that can cause persistent infection and adversely affect male reproductive health, an observation commonly attributed to deficiencies in inducible antiviral defence mechanisms. In this study, we demonstrate that interferon-epsilon (IFNε), a type I interferon initially discovered in female reproductive epithelia, is constitutively expressed by meiotic and post-meiotic spermatogenic cells, Leydig cells and macrophages in mouse testes. A similar distribution pattern was observed in human testes. Mice lacking IFNɛ were more susceptible to Zika virus-induced inflammation and damage of the testis and epididymis compared to wild-type mice. Exogenous IFNε treatment reduced the viral infection burden in cultured human testicular cells by inducing interferon-stimulated gene expression, and reducing inflammatory gene expression and cell damage. Treatment was more effective when administered prior to infection. These data indicate a critical role for constitutively-expressed IFNɛ in limiting viral infection and inflammatory damage in the male reproductive tract. Author summary: Many clinically significant viruses can infect the testis, affecting male fertility, and the health of the partners and children of infected men. Crucially, many viruses are transmitted via semen, because infections can elude the immune system by hiding in the testis, presumably because of its unique "immunologically privileged" environment. However, our understanding of anti-viral defences in the testis is lacking. We found that under normal physiological conditions, Interferon epsilon (IFNε), a novel antiviral molecule initially identified in the female reproductive tract, is expressed in testicular immune cells, but more significantly in cells that develop into sperm in both mice and humans. In this paper, we show that IFNε plays a crucial role in limiting Zika virus induced damage to the male reproductive system. [ABSTRACT FROM AUTHOR]

Background: Immunoregulatory genes encoding activin A (Inhba) and B (Inhbb), and indolamine 2,3‐dioxygenase‐1 (Ido1) are highly expressed in the murine caput epididymidis, which also has a network of intraepithelial mononuclear phagocytes. This environment is postulated to promote immunological tolerance to epididymal sperm. The factors regulating the immunoregulatory agents in the epididymal caput are poorly understood. Objectives: This study aimed to investigate the potential role of testicular lumicrine factors in regulating activin and other immune‐related genes in the caput epididymidis. Materials and methods: The efferent ducts in adult C57/Bl6 mice were exposed and ligated bilaterally. Serum and tissues were collected seven days later. Animals with bilateral sham ligation and animals with no ligations (collectively referred to as the "intact" group) were used as controls. Results: Pressure‐induced seminiferous epithelial damage due to intratubular fluid accumulation was observed in all ligated testes. Testicular inhibin was significantly increased and testosterone was elevated in some animals following bilateral ligation, but serum testosterone, serum LH, and serum inhibin were normal. Ligation caused epithelial regression in the initial segment, with similar but less severe effects in other caput segments. Activin A staining by immunohistochemistry in the epithelium was reduced in bilateral ligation, particularly in the initial segment, with moderately reduced staining intensity in the rest of the caput. Inhba expression within the caput was not significantly affected by bilateral ligation, but Inhbb was reduced by more than 60%. Transcripts encoding the macrophage‐specific receptor Cx3cr1 were significantly reduced following bilateral ligation, but other immune cell markers, Ido1, and inflammatory genes were unaffected. Conclusion: These data indicate that testicular lumicrine secretion regulates several genes that are preferentially expressed in the initial segment, but has marginal effects on genes such as those encoding activin A and IDO1, which are expressed more widely in the caput. [ABSTRACT FROM AUTHOR]