Complement Opsonization Promotes Herpes Simplex Virus 2 Infection of Human Dendritic Cells.

Elisa Crisci,Lena Serrander,Elin Rondahl,Sofia Nyström,Christopher Sjöwall,Kristina Eriksson,Rada Ellegård,Marie Larsson,Tomas Bergström,J U Jung

doi:10.1128/jvi.00224-16

Elisa Crisci, Lena Serrander + Show 8 more

Open Access

https://doi.org/10.1128/jvi.00224-16

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Abstract

ABSTRACTHerpes simplex virus 2 (HSV-2) is one of the most common sexually transmitted infections globally, with a very high prevalence in many countries. During HSV-2 infection, viral particles become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of immune responses. In genital mucosa, the primary target cells for HSV-2 infection are epithelial cells, but resident immune cells, such as dendritic cells (DCs), are also infected. DCs are the activators of the ensuing immune responses directed against HSV-2, and the aim of this study was to examine the effects opsonization of HSV-2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV-2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV-2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV-1- or HSV-2-specific antibodies more or less abolished HSV-2 infection of DCs. Our results clearly demonstrate the importance of studying HSV-2 infection under conditions that ensue in vivo, i.e., conditions under which the virions are covered in complement fragments and complement fragments and antibodies, as these shape the infection and the subsequent immune response and need to be further elucidated.IMPORTANCE During HSV-2 infection, viral particles should become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of the immune responses. The dendritic cells are activators of the immune responses directed against HSV-2, and the aim of this study was to examine the effects of complement alone or complement and antibodies on HSV-2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses. Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV-2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV-2 pathogenesis.

Highlights

Herpes simplex virus 2 (HSV-2) is one of the most common sexually transmitted infections globally, with a very high prevalence in many countries
The mRNA expression levels of HSV-2 thymidine kinase (TK), an enzyme involved in viral nucleotide biosynthesis and DNA metabolism, and glycoprotein D, a receptor that is part of the core fusion machinery and important in viral entry, were assessed by quantitative PCR (qPCR) at 6 h and 24 h postinfection (Fig. 1A and B)
The presence of HSV-1- or HSV-2-specific antibodies in the serum used for opsonization almost abolished infection, as seen in the decreased mRNA expression levels of TK and glycoprotein D (gD) compared to free virus and C-HSV-2 at both time points (Fig. 1A and B)

Summary

Introduction

Herpes simplex virus 2 (HSV-2) is one of the most common sexually transmitted infections globally, with a very high prevalence in many countries. During HSV-2 infection, viral particles should become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of the immune responses. HSV-2 gC facilitates virus entry by attaching the viral particle to host cell surface heparin sulfate and heparin [13], and the absence of gC sensitizes HSV-2 to lysis through the classical complement pathway in epithelial cells [14] It is clear from in vivo studies in different mouse models that the complement pathway plays an important role in HSV infection [15,16,17]. Individuals with HSV-1 immunity tend to remain asymptomatic for HSV-2 disease and to have their first clinical manifestation of genital herpes only after experiencing an immunosuppressive event [25]

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