Universität zu Köln

Petermann, Philipp, Thier, Katharina, Rahn, Elena, Rixon, Frazer J., Bloch, Wilhelm, Oezcelik, Semra, Krummenacher, Claude ORCID: 0000-0002-3492-4987, Barron, Martin J., Dixon, Michael J., Scheu, Stefanie ORCID: 0000-0002-9707-8191, Pfeffer, Klaus ORCID: 0000-0002-5652-6330 and Knebel-Moersdorf, Dagmar (2015). Entry Mechanisms of Herpes Simplex Virus 1 into Murine Epidermis: Involvement of Nectin-1 and Herpesvirus Entry Mediator as Cellular Receptors. J. Virol., 89 (1). S. 262 - 275. WASHINGTON: AMER SOC MICROBIOLOGY. ISSN 1098-5514

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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. How HSV-1 enters skin and whether both nectin-1 and HVEM are involved are not known. We addressed 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 of HVEM on the keratinocyte surface in epidermis and with the lack of HVEM expression in nectin-1-deficient primary keratinocytes. Our results suggest that nectin-1 is the primary receptor in epidermis, while HVEM has 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 of HVEM can potentially replace nectin-1 as a receptor, illustrating the flexibility employed by HSV-1 to efficiently invade tissue in vivo. IMPORTANCE Herpes simplex virus (HSV) can cause a range of diseases in humans, from uncomplicated mucocutaneous lesions to life-threatening infections. The skin is one target tissue of HSV, and the question of how the virus overcomes the protective skin barrier and penetrates into the tissue to reach its receptors is still open. Previous studies analyzing entry into cells grown in vitro revealed nectin-1 and HVEM as HSV receptors. To explore the contributions of nectin-1 and HVEM to entry into a natural target tissue, we established an ex vivo infection model. Using nectin-1-or HVEM-deficient mice, we demonstrated the distinct involvement of nectin-1 and HVEM for HSV-1 entry into epidermis and characterized the internalization pathways. Such advances in understanding the involvement of receptors in tissue are essential preconditions for unraveling HSV invasion of skin, which in turn will allow the development of antiviral reagents.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Petermann, Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Thier, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahn, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Rixon, Frazer J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bloch, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED Oezcelik, Semra UNSPECIFIED UNSPECIFIED UNSPECIFIED Krummenacher, Claude UNSPECIFIED orcid.org/0000-0002-3492-4987 UNSPECIFIED Barron, Martin J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dixon, Michael J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheu, Stefanie UNSPECIFIED orcid.org/0000-0002-9707-8191 UNSPECIFIED Pfeffer, Klaus UNSPECIFIED orcid.org/0000-0002-5652-6330 UNSPECIFIED Knebel-Moersdorf, Dagmar UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-419241
DOI:	10.1128/JVI.02917-14
Journal or Publication Title:	J. Virol.
Volume:	89
Number:	1
Page Range:	S. 262 - 275
Date:	2015
Publisher:	AMER SOC MICROBIOLOGY
Place of Publication:	WASHINGTON
ISSN:	1098-5514
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ADHESION MOLECULE NECTIN-1; GLYCOPROTEIN-D; PSEUDORABIES VIRUS; MAMMALIAN-CELLS; HEPARAN-SULFATE; ENDOCYTIC ENTRY; BINDING-SITE; MOUSE MODEL; TYPE-1; EXPRESSION Multiple languages Virology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41924