A STING-dependent innate-sensing pathway mediates resistance to corneal HSV-1 infection via upregulation of the antiviral effector tetherin.

Type 1 interferons (IFNs; IFNα/ß) mediate immunological host resistance to numerous viral infections, including herpes simplex virus type 1 (HSV-1). The pathways responsible for IFNα/ß signaling during the innate immune response to acute HSV-1 infection in the cornea are incompletely understood. Using a murine ocular infection model, we hypothesized that the stimulator of IFN genes (STING) mediates resistance to HSV-1 infection at the ocular surface and preserves the structural integrity of this mucosal site. Viral pathogenesis, tissue pathology, and host immune responses during ocular HSV-1 infection were characterized by plaque assay, esthesiometry, pachymetry, immunohistochemistry, flow cytometry, and small interfering RNA transfection in wild-type C57BL/6 (WT), STING-deficient (STING(-/-)), and IFNα/ß receptor-deficient (CD118(-/-)) mice at days 3-5 postinfection. The presence of STING was critical for sustained control of HSV-1 replication in the corneal epithelium and resistance to viral neuroinvasion, but loss of STING had a negligible impact with respect to gross tissue pathology. Auxiliary STING-independent IFNα/ß signaling pathways were responsible for maintenance of corneal integrity. Lymphatic vessels, mast cells, and sensory innervation were compromised in CD118(-/-) mice concurrent with increased tissue edema. STING-dependent signaling led to the upregulation of tetherin, a viral restriction factor we identify is important in containing the spread of HSV-1 in vivo.

IFN-α-driven CCL2 production recruits inflammatory monocytes to infection site in mice.

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.

Resistance to HSV-1 infection in the epithelium resides with the novel innate sensor, IFI-16.

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.

Chemokines and Chemokine Receptors Critical to Host Resistance following Genital Herpes Simplex Virus Type 2 (HSV-2) Infection.

HSV-2 is a highly successful human pathogen with a remarkable ability to elude immune detection or counter the innate and adaptive immune response through the production of viral-encoded proteins. In response to infection, resident cells secrete soluble factors including chemokines that mobilize and guide leukocytes including T and NK cells, neutrophils, and monocytes to sites of infection. While there is built-in redundancy within the system, chemokines signal through specific membrane-bound receptors that act as antennae detailing a chemical pathway that will provide a means to locate and eliminate the viral insult. Within the central nervous system (CNS), the temporal and spatial expression of chemokines relative to leukocyte mobilization in response to HSV-2 infection has not been elucidated. This paper will review some of the chemokine/chemokine receptor candidates that appear critical to the host in viral resistance and clearance from the CNS and peripheral tissue using murine models of genital HSV-2 infection.

Herpes simplex virus and the chemokines that mediate the inflammation.

Herpes simplex viruses (HSV) are highly pervasive pathogens in the human host with a seroconversion rate upwards of 60% worldwide. HSV type 1 (HSV-1) is associated with the disease herpetic stromal keratitis, the leading cause of infectious corneal blindness in the industrialized world. Individuals suffering from genital herpes associated with HSV type 2 (HSV-2) are found to be two- to threefold more susceptible in acquiring human immunodeficiency virus (HIV). The morbidity associated with these infections is principally due to the inflammatory response, the development of lesions, and scarring. Chemokines have become an important aspect in understanding the host immune response to microbial pathogens due in part to the timing of expression. In this paper, we will explore the current understanding of chemokine production as it relates to the orchestration of the immune response to HSV infection.

Molecular mimicry versus bystander activation: herpetic stromal keratitis.

Herpes stromal keratitis (HSK) is a significant inflammatory disease of the cornea as a result of herpes simplex virus (HSV) infection often progressing to vision loss if left untreated. However, even with immunosuppressive compounds and anti-viral drug treatment, HSV continues to be the leading cause of infectious corneal blindness in the industrialized world. The inflammatory nature of the disease is the root of the pathogenic process characterized by irreversible corneal scarring, neovascularization of the avascular cornea, and infiltration of activated leukocytes. Experimental evidence using mice suggest HSK is the result of either molecular mimicry or a bystander activation phenomenon. This review will revisit the basis of HSK focusing on issues that pertain to the autoimmune component versus collateral damage as a result of non-specific activation as a means to explain the pathologic manifestations of the disease.