RESUMO
The oral cavity is thought to be one of the portals for SARS-CoV-2 entry, although there is limited evidence of active oral infection by SARS-CoV-2 viruses. We assessed the capacity of SARS-CoV-2 to infect and replicate in oral epithelial cells. Oral gingival epithelial cells (hTERT TIGKs), salivary gland epithelial cells (A-253), and oral buccal epithelial cells (TR146), which occupy different regions of the oral cavity, were challenged with replication-competent SARS-CoV-2 viruses and with pseudo-typed viruses expressing SARS-CoV-2 spike proteins. All oral epithelial cells expressing undetectable or low levels of human angiotensin-converting enzyme 2 (hACE2) but high levels of the alternative receptor CD147 were susceptible to SARS-CoV-2 infection. Distinct viral dynamics were seen in hTERT TIGKs compared to A-253 and TR146 cells. For example, levels of viral transcripts were sustained in hTERT TIGKs but were significantly decreased in A-253 and TR146 cells on day 3 after infection. Analysis of oral epithelial cells infected by replication-competent SARS-CoV-2 viruses expressing GFP showed that the GFP signal and SARS-CoV-2 mRNAs were not evenly distributed. Furthermore, we found cumulative SARS-CoV-2 RNAs from released viruses in the media from oral epithelial cells on day 1 and day 2 after infection, indicating productive viral infection. Taken together, our results demonstrated that oral epithelial cells were susceptible to SARS-CoV-2 viruses despite low or undetectable levels of hACE2, suggesting that alternative receptors contribute to SARS-CoV-2 infection and may be considered for the development of future vaccines and therapeutics.
RESUMO
Interferon ε (IFNε) is a unique type I IFN that has been implicated in host defense against sexually transmitted infections (STIs). Zika virus (ZIKV), an emerging pathogen, can infect the female reproductive tract (FRT) and cause devastating diseases, particularly in pregnant women. How IFNε contributes to protection against ZIKV infection in vivo is unknown. Here, we show that IFNε plays a critical role in host protection against vaginal ZIKV infection in mice. We found that IFNε was expressed not only by epithelial cells in the FRT, but also by certain immune and other cells at baseline or after exposure to viruses or specific TLR agonists. IFNε-deficient mice exhibited abnormalities in the epithelial border and underlying tissue in the cervicovaginal tract, and these defects were associated with increased susceptibility to vaginal, but not subcutaneous ZIKV infection. IFNε-deficiency resulted in an increase in magnitude, duration, and depth of ZIKV infection in the FRT. Critically, intravaginal administration of recombinant IFNε protected Ifnε-/- mice and highly susceptible Ifnar1-/- mice against vaginal ZIKV infection, indicating that IFNε was sufficient to provide protection even in the absence of signals from other type I IFNs and in an IFNAR1-independent manner. Our findings reveal a potentially critical role for IFNε in mediating protection against transmission of ZIKV in the context of sexual contact.
RESUMO
Interferon É (IFNÉ) is a unique type I IFN that has been implicated in host defense against sexually transmitted infections. Zika virus (ZIKV), an emerging pathogen, can infect the female reproductive tract (FRT) and cause devastating diseases, particularly in pregnant women. How IFNÉ contributes to protection against ZIKV infection in vivo is unknown. In this study, we show that IFNÉ plays a critical role in host protection against vaginal ZIKV infection in mice. We found that IFNÉ was expressed not only by epithelial cells in the FRT but also by immune and stromal cells at baseline or after exposure to viruses or specific Toll-like receptor (TLR) agonists. IFNÉ-deficient mice exhibited abnormalities in the epithelial border and underlying tissue in the cervicovaginal tract, and these defects were associated with increased susceptibility to vaginal but not subcutaneous ZIKV infection. IFNÉ deficiency resulted in an increase in magnitude, duration, and depth of ZIKV infection in the FRT. Critically, intravaginal administration of recombinant IFNÉ protected IfnÉ-/- mice and highly susceptible Ifnar1-/- mice against vaginal ZIKV infection, indicating that IFNÉ was sufficient to provide protection even in the absence of signals from other type I IFNs and in an IFNAR1-independent manner. Our findings reveal a potentially critical role for IFNÉ in mediating protection against the transmission of ZIKV in the context of sexual contact.