Evasion of the mucosal innate immune system by herpes simplex virus type 2.
Understanding the mechanisms by which herpes simplex virus (HSV) evades host immune defenses is critical to defining new approaches for therapy and prevention. We performed transcriptional analyses and immunocytochemistry on sequential biopsy specimens of lesional tissue from the acute through the posthealing phases of recurrent mucocutaneous HSV-2 infection. Histological analysis of these biopsy specimens during the acute stage revealed a massive infiltration of T cells, as well as monocytes/macrophages, a large amount of myeloid, and a small number of plasmacytoid dendritic cells, in the dermis of these lesional biopsy specimens. Type I interferon (IFN-beta and IFN-alpha) was poorly expressed and gamma IFN (IFN-gamma) potently induced during time periods in which we detected abundant amounts of HSV-2 antigens and HSV-2 RNA. IFN-stimulated genes were also markedly upregulated, with expression patterns that more closely matched those in primary human fibroblasts treated by IFN-gamma than those in fibroblasts treated by IFN-beta. Transcriptional arrays of the same lesional biopsy sites during healing and at 2 and 4 weeks posthealing revealed no HSV nucleic acids or antigen; however, there was persistent expression of IFN-gamma, with very low levels of IFN-beta and IFN-alpha. The findings of extremely low levels of IFN-alpha and IFN-beta, despite the presence of a large number of cells capable of synthesizing these substances, suggest a potent alteration in host defense during HSV-2 infection in vivo. HSV-2's blockade of the innate immune system's production of type I IFN may be a major factor in allowing the virus to break through host mucosal defenses.
Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Tao
T
Peng
Jia
J
Zhu
Alexis
A
Klock
Khamsone
K
Phasouk
Meei-Li
ML
Huang
David M
DM
Koelle
Anna
A
Wald
Lawrence
L
Corey
D001706:Biopsy; D003713:Dendritic Cells / Q000276:immunology; D020869:Gene Expression Profiling; D006558:Herpes Genitalis / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000276:immunology*; D006801:Humans; D018928:Immunity, Mucosal; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000096:biosynthesis; D016899:Interferon-beta / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology; D009092:Mucous Membrane / Q000276:immunology* / Q000821:virology*; D012867:Skin / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology
D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma