| First Author | Coldbeck-Shackley RC | Year | 2023 |
| Journal | PLoS Pathog | Volume | 19 |
| Issue | 3 | Pages | e1010843 |
| PubMed ID | 36897927 | Mgi Jnum | J:334635 |
| Mgi Id | MGI:7447889 | Doi | 10.1371/journal.ppat.1010843 |
| Citation | Coldbeck-Shackley RC, et al. (2023) Constitutive expression and distinct properties of IFN-epsilon protect the female reproductive tract from Zika virus infection. PLoS Pathog 19(3):e1010843 |
| abstractText | The immunological surveillance factors controlling vulnerability of the female reproductive tract (FRT) to sexually transmitted viral infections are not well understood. Interferon-epsilon (IFNvarepsilon) is a distinct, immunoregulatory type-I IFN that is constitutively expressed by FRT epithelium and is not induced by pathogens like other antiviral IFNs alpha, beta and lambda. We show the necessity of IFNvarepsilon for Zika Virus (ZIKV) protection by: increased susceptibility of IFNvarepsilon-/- mice; their "rescue" by intravaginal recombinant IFNvarepsilon treatment and blockade of protective endogenous IFNvarepsilon by neutralising antibody. Complementary studies in human FRT cell lines showed IFNvarepsilon had potent anti-ZIKV activity, associated with transcriptome responses similar to IFNlambda but lacking the proinflammatory gene signature of IFNalpha. IFNvarepsilon activated STAT1/2 pathways similar to IFNalpha and lambda that were inhibited by ZIKV-encoded non-structural (NS) proteins, but not if IFNepsilon exposure preceded infection. This scenario is provided by the constitutive expression of endogenous IFNepsilon. However, the IFNvarepsilon expression was not inhibited by ZIKV NS proteins despite their ability to antagonise the expression of IFNbeta or lambda. Thus, the constitutive expression of IFNvarepsilon provides cellular resistance to viral strategies of antagonism and maximises the antiviral activity of the FRT. These results show that the unique spatiotemporal properties of IFNepsilon provides an innate immune surveillance network in the FRT that is a significant barrier to viral infection with important implications for prevention and therapy. |
