RESUMO
Herpes simplex virus type 1 (HSV-1) is the leading cause of corneal blindness in the developed world due to reactivation of infectious virus and the subsequent immune response. The innate response that facilitates viral control in the cornea is currently unknown. In the present study using a mouse chimera model, we found that a bone marrow component is crucial in inhibiting viral replication and identified inflammatory monocytes (F4/80(+) Gr1(+)) as the responsible cell. CCL2 was critical for recruiting inflammatory monocytes, and a loss of this chemokine in CCL2(-/-) mice resulted in a loss of viral containment and inflammatory monocyte recruitment. To confirm these results, clodronate depletion of inflammatory monocytes resulted in elevated viral titers. Furthermore, siRNA targeting the innate sensor p204/IFI-16 resulted in a loss of CCL2 production. In conclusion, CCL2 expression driven by IFI-16 recognition of HSV-1 facilitates the recruitment of inflammatory monocytes into the cornea proper to control viral replication.
Assuntos
Quimiocina CCL2/biossíntese , Inflamação/imunologia , Inflamação/metabolismo , Interferon-alfa/metabolismo , Animais , Córnea/imunologia , Córnea/metabolismo , Córnea/virologia , Feminino , Herpesvirus Humano 1/imunologia , Inflamação/genética , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/imunologia , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Masculino , Camundongos , Camundongos Knockout , Modelos Imunológicos , Monócitos/imunologia , Monócitos/metabolismo , Óxido Nítrico/biossíntese , Replicação ViralRESUMO
Toll-like receptors (TLRs) are innate sentinels required for clearance of bacterial and fungal infections of the cornea, but their role in viral immunity is currently unknown. We report that TLR signaling is expendable in herpes simplex virus (HSV)-1 containment as depicted by plaque assays of knockout mice (MyD88(-/-), Trif(-/-) and MyD88(-/-) Trif(-/-) double knockout) resembling wild-type controls. To identify the key sentinel in viral recognition of the cornea, in vivo knockdown of the DNA sensor IFI-16/p204 in the corneal epithelium was performed and resulted in a loss of IFN-regulatory factor-3 (IRF-3) nuclear translocation, interferon-α production, and viral containment. The sensor seems to have a similar function in other HSV clinically relevant sites such as the vaginal mucosa in which a loss of p204/IFI-16 results in significantly more HSV-2 shedding. Thus, we have identified an IRF-3-dependent, IRF-7- and TLR-independent innate sensor responsible for HSV containment at the site of acute infection.
