Type I interferon production during herpes simplex virus infection is controlled by cell-type-specific viral recognition through Toll-like receptor 9, the mitochondrial antiviral signaling protein pathway, and novel recognition systems.
Recognition of viruses by germ line-encoded pattern recognition receptors of the innate immune system is essential for rapid production of type I interferon (IFN) and early antiviral defense. We investigated the mechanisms of viral recognition governing production of type I IFN during herpes simplex virus (HSV) infection. We show that early production of IFN in vivo is mediated through Toll-like receptor 9 (TLR9) and plasmacytoid dendritic cells, whereas the subsequent alpha/beta IFN (IFN-alpha/beta) response is derived from several cell types and induced independently of TLR9. In conventional DCs, the IFN response occurred independently of viral replication but was dependent on viral entry. Moreover, using a HSV-1 UL15 mutant, which fails to package viral DNA into the virion, we found that entry-dependent IFN induction also required the presence of viral genomic DNA. In macrophages and fibroblasts, where the virus was able to replicate, HSV-induced IFN-alpha/beta production was dependent on both viral entry and replication, and ablated in cells unable to signal through the mitochondrial antiviral signaling protein pathway. Thus, during an HSV infection in vivo, multiple mechanisms of pathogen recognition are active, which operate in cell-type- and time-dependent manners to trigger expression of type I IFN and coordinate the antiviral response.
Rasmussen
Simon B
SB
Institute of Medical Microbiology and Immunology, The Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark.
Sørensen
Louise N
LN
Malmgaard
Lene
L
Ank
Nina
N
Baines
Joel D
JD
Chen
Zhijian J
ZJ
Paludan
Søren R
SR
D000818:Animals; D000998:Antiviral Agents / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000821:virology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000821:virology; D005786:Gene Expression Regulation; D006561:Herpes Simplex / Q000276:immunology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis; D016899:Interferon-beta / Q000096:biosynthesis; D007739:L Cells; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D011817:Rabbits; D013154:Spleen / Q000166:cytology / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells; D014779:Virus Replication
D000998:Antiviral Agents; D007370:Interferon Type I; D016898:Interferon-alpha; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D016899:Interferon-beta