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.
Article: Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency.[show abstract] [hide abstract]
ABSTRACT: Reactivation of herpes simplex virus type 1 (HSV-1) from neuronal latency is a common and potentially devastating cause of disease worldwide. CD8+ T cells can completely inhibit HSV reactivation in mice, with interferon-gamma affording a portion of this protection. We found that CD8+ T cell lytic granules are also required for the maintenance of neuronal latency both in vivo and in ex vivo ganglia cultures and that their directed release to the junction with neurons in latently infected ganglia did not induce neuronal apoptosis. Here, we describe a nonlethal mechanism of viral inactivation in which the lytic granule component, granzyme B, degrades the HSV-1 immediate early protein, ICP4, which is essential for further viral gene expression.Science 11/2008; 322(5899):268-71. · 31.20 Impact Factor
Article: IL-4 promotes airway eosinophilia by suppressing IFN-gamma production: defining a novel role for IFN-gamma in the regulation of allergic airway inflammation.[show abstract] [hide abstract]
ABSTRACT: Airway eosinophilia in asthma is dependent on cytokines secreted by Th2 cells, including IL-5 and IL-4. In these studies we investigated why the absence of IL-4 led to a reduction in airway, but not lung tissue, eosinophils. Using adoptively transferred, in vitro-generated TCR-transgenic Th2 cells deficient in IL-4, we show that this effect is independent of IL-5 and Th2 cell generation. Airway eosinophilia was no longer inhibited when IL-4(-/-) Th2 cells were transferred into IFN-gammaR(-/-) mice, indicating that IFN-gamma was responsible for reducing airway eosinophils in the absence of IL-4. Intranasal administration of IFN-gamma to mice after IL-4(+/+) Th2 cell transfer also caused a reduction in airway, but not lung parenchymal, eosinophils. These studies show that IL-4 indirectly promotes airway eosinophilia by suppressing the production of IFN-gamma. IFN-gamma reduces airway eosinophils by engaging its receptor on hemopoietic cells, possibly the eosinophil itself. These studies capitalize on the complex counterregulatory effects of Th1 and Th2 cytokines in vivo and clarify how IL-4 influences lung eosinophilia. We define a new regulatory role for IFN-gamma, demonstrating that eosinophilic inflammation is differentially regulated at distinct sites within the respiratory tract.The Journal of Immunology 03/2001; 166(4):2760-7. · 5.79 Impact Factor
Article: Herpes simplex virus ICP0 and ICP34.5 counteract distinct interferon-induced barriers to virus replication.[show abstract] [hide abstract]
ABSTRACT: Interferon inhibits virus replication through multiple mechanisms. Here we show that herpes simplex virus proteins ICP0 and ICP34.5 overcome interferon-induced barriers to viral transcription and translation, respectively. These cytokine-induced antiviral mechanisms are differentially expressed in established cell lines: U2OS cells do not mount the IFN-induced mechanism targeted by ICP0, and Vero cells may be defective for the mechanism targeted by ICP34.5.Journal of Virology 03/2002; 76(4):1995-8. · 5.40 Impact Factor