Herpes simplex virus 2-induced activation in vaginal cells involves Toll-like receptors 2 and 9 and DNA sensors DAI and IFI16.
OBJECTIVE
The pathway by which herpes simplex virus 2 (HSV2) triggers the innate immune system in the urogenital system has not as yet been fully elucidated. In this study, we aimed to determine which pattern recognition receptors (PRRs) recognize HSV2 in primary vaginal epithelial cells. Once we deciphered the receptors involved, we aimed to target them to immunomodulate innate responses as a prophylactic or therapeutic intervention for early HSV2 infection.


METHODS
To determine which PRRs are involved, receptor silencing as well as confocal microscopy was utilized. For immunomodulation, PRR agonists were utilized to induce a strong, local response to limit the infection, and we used 2 quantitative methods, flow cytometry and plaque assays, to determine their effect on HSV2 replication.


RESULTS
Our results show that HSV2 is detected by a plethora of PRRs: Toll-like receptors (TLR) 2 as well as deoxyribonucleic acid (DNA) sensors TLR9, DNA-dependent activator of interferon regulatory factors, and to a lesser extent interferon-inducible 16, which trigger cytokine secretion to protect the host. Using PRR agonists, such as lipoproteins, CpG DNA, and cyclic dinucleotides, we could significantly limit HSV2 replication.


CONCLUSIONS
Different PRRs are strategically placed in different cell locations to detect virus invasion. Use of agonists that target and activate these PRRs appeared to be effective in preventing primary HSV2 infection in vaginal cells and could provide new insights in defense against HSV2 urogenital infections.
Institute of Infection and Immunity, School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, Wales, UK.
Kathy
K
Triantafilou
Institute of Infection and Immunity, School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, Wales, UK.
Dilan
D
Eryilmazlar
Institute of Infection and Immunity, School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, Wales, UK. Electronic address: TriantafilouM@cardiff.ac.uk.
Martha
M
Triantafilou
D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D006558:Herpes Genitalis / Q000276:immunology / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D009687:Nuclear Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D016601:RNA-Binding Proteins; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000502:physiology; D014621:Vagina / Q000276:immunology / Q000821:virology; D014775:Virus Activation / Q000502:physiology*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; C485731:ZBP1 protein, human; C076700:IFI16 protein, human
Toll-like receptor 9; genital infection; herpes simplex virus 2; innate immunity