Herpes simplex type I (HSV-1) infection of the nervous system: is an immune response a good thing?

Abstract

Herpes simplex virus type 1 (HSV-1) can induce a robust immune response initially thru the activation of pattern recognition receptors and subsequent type I interferon production that then shapes, along with other innate immune components, the adaptive immune response to the insult. While this response is necessary to quell virus replication, drive the pathogen into a "latent" state, and likely hinder viral reactivation, collateral damage can ensue with demonstrable cell death and foci of tissue pathology in the central nervous system (CNS) as a result of the release of inflammatory mediators including reactive oxygen species. Although rare, HSV-1 is the leading cause of frank sporadic encephalitis that, if left untreated, can result in death. A greater understanding of the contribution of resident glial cells and infiltrating leukocytes within the CNS in response to HSV-1 invasion is necessary to identify candidate molecules as targets for therapeutic intervention to reduce unwarranted inflammation coinciding with the maintenance of the anti-viral state.

Figure 1

Mechanisms of HSV-1-mediated antagonism of TLR-dependent, anti-viral pathways. TLR-3 signals in a MYD88-independent manner to induce interferon production, while TLR-9 activates inflammatory cytokines and interferons through a MYD88-dependent pathway in response to HSV-1 infection. HSV-1 blocks ND10 accumulation in the nucleus, PKR activity, and Jak/STAT signaling with a cumulative effect that renders the infected cell highly susceptible to viral replication.

Figure 2

The absence of a functional type I IFN receptor results in a massive loss of cells populating the draining (mandibular) lymph node following ocular HSV-1 infection. Wild type and IFNRA1 deficient mice (CD118-/-) were infected with 1,000 plaque forming units of HSV-1 (McKrae strain) in the cornea. Five days post infection, the mice were exsanguinated and the mandibular lymph nodes were removed, sectioned, and H&E stained. The results are representative of three experiments, two mice/group/experiment. (a) Wild type mouse lymph node showing normal lymph node integrity at 40x magnification and (b) 100x magnification. (c) Lymph node from a CD118^-/- mouse with widespread cell death resulting in a loss of cells at 40x magnification, and (d) 100x magnification.

Figure 3

Type I IFN receptor deficient mice show increased expression of HSV-1 antigen and reduced CD3⁺ T cell infiltration in the trigeminal ganglia following ocular infection with HSV-1. Wild type and IFNRA1 deficient mice (CD118-/-) were infected with 1,000 plaque forming units of HSV-1 (McKrae strain) in the cornea. Five days post infection, the mice were exsanguinated and the trigeminal ganglia were removed and processed for whole mount staining using polyclonal phycoerythrin-conjugated anti-HSV-1 (red) and fluorescein isothiocyanate-conjugated anti-CD3 (green) antibodies. (a) Trigeminal ganglion of a wild type mouse at 400x magnification showing T cell infiltration with little appreciable HSV-1 antigen expression. (b) Trigeminal ganglion from a CD118^-/- mouse at magnification of 400x with a constellation of HSV-1 antigen expression but few T cells residing in the tissue. Nuclei were stained with DAPI (blue). This figure is representative of three trigeminal ganglia per group.