Herpes Simplex Virus type 1 infects Langerhans cells and the novel epidermal dendritic cell, Epi-cDC2s, via different entry pathways

Kirstie M Bertram,Hafsa Rana,Jake Lim,Min Kim,Steven L Merten,Kerrie J Sandgren,Naomi R Truong,Kevin Danastas,Andrew N Harman,Jason J Herbert,Jake W Rhodes,Jacinta B Smith,Anthony L Cunningham,Ralph C Cohen,Monica Miranda-Saksena,Ellis Patrick,Konrad L Feng,Donna Neumann

doi:10.1371/journal.ppat.1009536

Abstract

Skin mononuclear phagocytes (MNPs) provide the first interactions of invading viruses with the immune system. In addition to Langerhans cells (LCs), we recently described a second epidermal MNP population, Epi-cDC2s, in human anogenital epidermis that is closely related to dermal conventional dendritic cells type 2 (cDC2) and can be preferentially infected by HIV. Here we show that in epidermal explants topically infected with herpes simplex virus (HSV-1), both LCs and Epi-cDC2s interact with HSV-1 particles and infected keratinocytes. Isolated Epi-cDC2s support higher levels of infection than LCs in vitro, inhibited by acyclovir, but both MNP subtypes express similar levels of the HSV entry receptors nectin-1 and HVEM, and show similar levels of initial uptake. Using inhibitors of endosomal acidification, actin and cholesterol, we found that HSV-1 utilises different entry pathways in each cell type. HSV-1 predominantly infects LCs, and monocyte-derived MNPs, via a pH-dependent pathway. In contrast, Epi-cDC2s are mainly infected via a pH-independent pathway which may contribute to the enhanced infection of Epi-cDC2s. Both cells underwent apoptosis suggesting that Epi-cDC2s may follow the same dermal migration and uptake by dermal MNPs that we have previously shown for LCs. Thus, we hypothesize that the uptake of HSV and infection of Epi-cDC2s will stimulate immune responses via a different pathway to LCs, which in future may help guide HSV vaccine development and adjuvant targeting.

Highlights

Herpes Simplex Virus type 1 (HSV-1) causes orofacial and genital herpes as well as encephalitis, neonatal herpes, and keratitis and blindness
It was previously thought that this initial interaction of HSV-1 was only with ‘Langerhans cells’ (LCs) but we describe another important interaction with a new immune cell, Epi-conventional dendritic cells type 2 (cDC2), which can be infected by HIV and much more efficiently than LCs
We showed that LCs become infected with HSV-1, and more recently that a second subset of mononuclear phagocytes (MNPs) resides in the epidermis, CD11c+ Epi-cDC2s

Summary

Introduction

Herpes Simplex Virus type 1 (HSV-1) causes orofacial and genital herpes as well as encephalitis, neonatal herpes, and keratitis and blindness. HSV-2 causes genital herpes and predisposes to HIV acquisition. Like HSV-2, HSV-1 can enter the stratified squamous oral and genital mucosa via the superficial epidermis, which consists mainly of keratinocytes, through minor abrasions. Keratinocytes are a formidable barrier to pathogen entry and form the keratinized superficial stratum corneum. Beneath this they are the major target for HSV infection, as they express nectin-1 which facilitates HSV entry. The stratum corneum is thin over the inner foreskin and labia and absent from the ectocervix, vagina and anus allowing easier viral entry into the epidermis [1,2]

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