A majority of the world population is infected with herpes simplex viruses (HSV; human herpesvirus types 1 and 2). These viruses, perhaps best known for their manifestation in the genital or oral mucosa, can also cause herpes simplex encephalitis, a severe and often fatal disease of the central nervous system. Antiviral therapies for HSV are only partially effective since the virus can establish latent infections in neurons, and severe pathological sequelae in the brain are common. A better understanding of disease pathogenesis is required to develop new strategies against herpes simplex encephalitis, including the precise viral and host genetic determinants that promote virus invasion into the central nervous system and its associated immunopathology. Here we review the current understanding of herpes simplex encephalitis from the host genome perspective, which has been illuminated by groundbreaking work on rare herpes simplex encephalitis patients together with mechanistic insight from single-gene mouse models of disease. A complex picture has emerged, whereby innate type I interferon-mediated antiviral signaling is a central pathway to control viral replication, and the regulation of immunopathology and the balance between apoptosis and autophagy are critical to disease severity in the central nervous system. The lessons learned from mouse studies inform us on fundamental defense mechanisms at the interface of host–pathogen interactions within the central nervous system, as well as possible rationales for intervention against infections from severe neuropathogenic viruses.
The continuous interactions between host and pathogens during their coevolution have shaped both the immune system and the countermeasures used by pathogens. Natural killer (NK) cells are innate lymphocytes that are considered central players in the antiviral response. Not only do they express a variety of inhibitory and activating receptors to discriminate and eliminate target cells but they can also produce immunoregulatory cytokines to alert the immune system. Reciprocally, several unrelated viruses including cytomegalovirus, human immunodeficiency virus, influenza virus, and dengue virus have evolved a multitude of mechanisms to evade NK cell function, such as the targeting of pathways for NK cell receptors and their ligands, apoptosis, and cytokine-mediated signaling. The studies discussed in this article provide further insights into the antiviral function of NK cells and the pathways involved, their constituent proteins, and ways in which they could be manipulated for host benefit.
Herpes simplex encephalitis (HSE), caused by HSV type 1 (HSV-1) infection, is an acute neuroinflammatory condition of the CNS and remains the most common type of sporadic viral encephalitis worldwide. Studies in humans have shown that susceptibility to HSE depends in part on the genetic make-up of the host, with deleterious mutations in the TLR3/type I IFN axis underlying some cases of childhood HSE. Using an in vivo chemical mutagenesis screen for HSV-1 susceptibility in mice, we identified a susceptible pedigree carrying a causal truncating mutation in the Rel gene (Rel C307X), encoding for the NF-kB transcription factor subunit c-Rel. Like Myd88 2/2 and Irf3 2/2 mice, Rel C307X mice were susceptible to intranasal HSV-1 infection. Reciprocal bone marrow transfers into lethally irradiated hosts suggested that defects in both hematopoietic and CNS-resident cellular compartments contributed together to HSE susceptibility in Rel C307X mice. Although the Rel C307X mutation maintained cell-intrinsic antiviral control, it drove increased apoptotic cell death in infected fibroblasts. Moreover, reduced numbers of CD4 + CD25 + Foxp3 + T regulatory cells, and dysregulated NK cell and CD4 + effector T cell responses in infected Rel C307X animals, indicated that protective immunity was also compromised in these mice. In the CNS, moribund Rel C307X mice failed to control HSV-1 viral replication in the brainstem and cerebellum, triggering cell death and elevated expression of Ccl2, Il6, and Mmp8 characteristic of HSE neuroinflammation and pathology. In summary, our work implicates c-Rel in both CNS-resident cell survival and lymphocyte responses to HSV-1 infection and as a novel cause of HSE disease susceptibility in mice.
The T cell specific adapter protein (TSAd) is expressed in activated T cells and NK cells. While TSAd is beginning to emerge as a critical regulator of Lck and Itk activity in T cells, its role in NK cells has not yet been explored. Here we have examined susceptibility to virus infections in a murine model using various viral infection models. We report that TSAd-deficient mice display reduced clearance of murine cytomegalovirus (MCMV) that lack the viral MHC class I homologue m157, which is critical for Ly49H-mediated NK cell recognition of infected cells. In this infection model, NK cells contribute in the early stages of the disease, whereas CD8+ T cells are critical for viral clearance. We found that mice infected with MCMV Δm157 displayed reduced viral clearance in the spleen as well as reduced proliferation in spleen NK cells and CD8+ T cells in the absence of TSAd. Though no other immunophenotype was detected in the infection models tested, these data suggests that in the absence of the Ly49H ligand activation, NK cell and CD8+ T cell responses may be compromised in TSAd-deficient mice.
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