Entry mechanisms of herpes simplex virus 1 into murine epidermis: Involvement of nectin-1 and herpesvirus entry mediator as cellular receptors

Philipp Petermann, Katharina Thier, Elena Rahn, Frazer J. Rixon, Wilhelm Bloch, Semra Özcelik, Claude Krummenacher, Martin J. Barron, Michael J. Dixon, Stefanie Scheu, Klaus Pfeffer, Dagmar Knebel-Mörsdorf

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Skin keratinocytes represent a primary entry site for herpes simplex virus 1 (HSV-1) in vivo. The cellular proteins nectin-1 and herpesvirus entry mediator (HVEM) act as efficient receptors for both serotypes of HSV and are sufficient for disease development mediated by HSV-2 in mice.HowHSV-1 enters skin and whether both nectin-1 andHVEMare involved are not known.Weaddressed the impact of nectin-1 during entry of HSV-1 into murine epidermis and investigated the putative contribution of HVEM. Using ex vivo infection of murine epidermis, we showed that HSV-1 entered the basal keratinocytes of the epidermis very efficiently. In nectin-1-deficient epidermis, entry was strongly reduced. Almost no entry was observed, however, in nectin-1-deficient keratinocytes grown in culture. This observation correlated with the presence ofHVEMon the keratinocyte surface in epidermis and with the lack ofHVEM expression in nectin-1-deficient primary keratinocytes. Our results suggest that nectin-1 is the primary receptor in epidermis, while HVEMhas a more limited role. For primary murine keratinocytes, on which nectin-1 acts as a single receptor, electron microscopy suggested that HSV-1 can enter both by direct fusion with the plasma membrane and via endocytic vesicles. Thus, we concluded that nectin-1 directs internalization into keratinocytes via alternative pathways. In summary, HSV-1 entry into epidermis was shown to strongly depend on the presence of nectin-1, but the restricted presence ofHVEMcan potentially replace nectin-1 as a receptor, illustrating the flexibility employed by HSV-1 to efficiently invade tissue in vivo.

Original languageEnglish (US)
Pages (from-to)262-274
Number of pages13
JournalJournal of virology
Volume89
Issue number1
DOIs
StatePublished - 2015

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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