The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice Is a Major Cause of Central Nervous System Pathology Resulting in Fatal Encephalitis (original) (raw)

Role of Specific Innate Immune Responses in Herpes Simplex Virus Infection of the Central Nervous System

Journal of Virology, 2011

Herpes simplex virus 1 (HSV-1) causes a spectrum of disease, including herpes labialis, herpes keratitis, and herpes encephalitis, which can be lethal. Viral recognition by pattern recognition receptors plays a central role in cytokine production and in the generation of antiviral immunity. The relative contributions of different Toll-like receptors (TLRs) in the innate immune response during central nervous system infection with HSV-1 have not been fully characterized. In this study, we investigate the roles of TLR2, TLR9, UNC93B1, and the type I interferon (IFN) receptor in a murine model of HSV-1 encephalitis. TLR2 is responsible for detrimental inflammatory cytokine production following intracranial infection with HSV-1, and the absence of TLR2 expression leads to increased survival in mice. We prove that inflammatory cytokine production by microglial cells, astrocytes, neutrophils, and monocytes is mediated predominantly by TLR2. We also demonstrate that type I IFNs are absolut...

Alteration of intracerebral cytokine production in mice infected with herpes simplex virus types 1 and 2

Journal of Neuroimmunology, 1994

Previously we reported that a lethal strain of herpes simplex virus type 2 (HSV-2) infects the brain following ocular inoculation of mice. We now demonstrate that HSV-2 mediates an unusual intracellular sequestering of class II major histocompatibility complex (MHC) antigens. With use of an RNase protection assay, we observed a selective inhibition of IFN-y and IL-6 gene transcfil~tion in brains of mice infected with HSV-2. It is likely that the inhibition of cytokine gene expression was mediated through a failure to activate CD4 + lymphocytes. These data suggest that the infecting herpesvirus can influence the profile of intracerebrally produced cytokines, which in turn may determine the outcome of the infection.

The heterogeneity in the immune response and efficiency of viral dissemination in brain infected with herpes simplex virus type 1 through peripheral or central route

Acta Neuropathologica, 1999

Using immunohistochemistry on adjacent brain sections, we studied the correlation between the dissemination of the virus, the inflammatory responses and the expression of major histocompatibility complex (MHC) proteins in rat brain infected with herpes simplex virus (HSV-1) F strain by either corneal scarification or intracerebral injection. Our results showed that the mortality of the corneally infected rats was much higher than that of the intracerebrally infected rats, due to a more extensive dissemination of the virus in the brain, particularly in the brain stem. The inflammatory responses were similar in brains infected through either route, as demonstrated by the expression of MHC I/II antigens on infiltrating lymphocytes, leukocytes and macrophage/microglia cells. While there was strong immunoreactivity for HSV-1 antigens in the cerebral cortex, the infiltrates were only located in subcortical areas, especially the hippocampus. Therefore, the distribution of these immune cells did not always overlap with the regions of viral infection. These results suggest that HSV-1 disseminate more efficiently from the peripheral to the central nervous system (CNS) than from CNS to CNS, which is independent of the immune responses, and that the cerebral cortex may immunologically respond to HSV-1 infection differently from other brain regions.

Lethal Encephalitis in Myeloid Differentiation Factor 88Deficient Mice Infected with Herpes Simplex Virus 1

American Journal of Pathology, 2005

Herpes simplex virus 1 (HSV-1), a large DNA virus from the Herpesviridae family, is the major cause of sporadic lethal encephalitis and blindness in humans. Recent studies have shown the importance of Toll-like receptors (TLRs) in the immune response to HSV-1 infection. Myeloid differentiation factor 88 (MyD88) is a critical adaptor protein that is downstream to mediated TLR activation and is essential for the production of inflammatory cytokines. Here, we studied the relationship between MyD88 and HSV-1 using a purified HSV-1 isolated from a natural oral recurrent human infection. We observed the activation of TLR-2 by HSV-1 in vitro using Chinese hamster ovary cells stably transfected with a reporter gene. Interestingly, we found that only peritoneal macrophages from MyD88−/− mice, but not macrophages from TRL2−/− or from wild-type mice, were unable to produce tumor necrosis factor-α in response to HSV-1 exposure. Additionally, although TLR2−/− mice showed no enhanced susceptibility to intranasal infection with HSV-1, MyD88−/− mice were highly susceptible to infection and displayed viral migration to the brain, severe neuropathological signs of encephalitis, and 100% mortality by day 10 after infection. Together, our results suggest that innate resistance to HSV-1 is mediated by MyD88 and may rely on activation of multiple TLRs.

Herpes Simplex Virus 1 Infection of Neuronal and Non-Neuronal Cells Elicits Specific Innate Immune Responses and Immune Evasion Mechanisms

Frontiers in Immunology, 2021

Alphaherpesviruses (a-HV) are a large family of double-stranded DNA viruses which cause many human and animal diseases. There are three human a-HVs: Herpes Simplex Viruses (HSV-1 and HSV-2) and Varicella Zoster Virus (VZV). All a-HV have evolved multiple strategies to suppress or exploit host cell innate immune signaling pathways to aid in their infections. All a-HVs initially infect epithelial cells (primary site of infection), and later spread to infect innervating sensory neurons. As with all herpesviruses, a-HVs have both a lytic (productive) and latent (dormant) stage of infection. During the lytic stage, the virus rapidly replicates in epithelial cells before it is cleared by the immune system. In contrast, latent infection in host neurons is a lifelong infection. Upon infection of mucosal epithelial cells, herpesviruses immediately employ a variety of cellular mechanisms to evade host detection during active replication. Next, infectious viral progeny bud from infected cells and fuse to neuronal axonal terminals. Here, the nucleocapsid is transported via sensory neuron axons to the ganglion cell body, where latency is established until viral reactivation. This review will primarily focus on how HSV-1 induces various innate immune responses, including host cell recognition of viral constituents by pattern-recognition receptors (PRRs), induction of IFN-mediated immune responses involving toll-like receptor (TLR) signaling pathways, and cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING). This review focuses on these pathways along with other mechanisms including autophagy and the complement system. We will summarize and discuss recent evidence which has revealed how HSV-1 is able to manipulate and evade host antiviral innate immune responses both in neuronal (sensory neurons of the trigeminal ganglia) and nonneuronal (epithelial) cells. Understanding the innate immune response mechanisms triggered by HSV-1 infection, and the mechanisms of innate immune evasion, will impact the development of future therapeutic treatments.

Role of IL-4 in an experimental model of encephalitis induced by intracranial inoculation of herpes simplex virus-1 (HSV-1)

Arquivos de Neuro-Psiquiatria, 2011

Herpes simplex virus-1 (HSV-1) is a pathogen that may cause severe encephalitis in humans. In this study, we aimed to investigate the role of interleukin-4 (IL-4) in a model of HSV-1 brain infection. IL-4 knockout (IL-4 -/-) and wild type (WT) C57BL/6 mice were inoculated with 10 4 plaque-forming units of HSV-1 by the intracranial route. Histopathologic analysis revealed a distinct profile of infiltrating cells at 3 days postinfection (dpi). Infected WT mice presented mononuclear inflammatory cells while IL-4 -/mice developed meningoencephalitis with predominance of neutrophils. IL-4 -/mice had diminished leukocyte adhesion at 3 dpi when compared to infected WT animals in intravital microscopy study. Conversely no differences were found in cerebral levels of CXCL1, CXCL9, CCL3, CCL5 and TNF-α between WT and IL-4 -/infected mice. IL-4 may play a role in the recruitment of cells into central nervous system in this acute model of severe encephalitis caused by HSV-1.

Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

Journal of Virology, 2013

We have reported previously that ocular infection of different strains of mice with recombinant 21 HSV-1 constitutively expressing IL-2 provokes CNS demyelination and optic neuropathy as determined 22 by changes in visual-evoked cortical potentials and pathologic changes in the optic nerve and CNS, 23 whereas recombinant viruses expressing IL-4, IFN-γ, IL-12p35, IL-12p40, or IL-12p70 do not induce 24 this neuropathy. The goal of this study was to dissect the mechanism underlying the interplay between 25 the immune system (elevation of IL-2) and an environmental factor (infection with HSV-1) that elicit this 26 pathology. Similar results were obtained upon delivery of IL-2 into the mouse brain using osmotic mini-27 pumps or injection of mice with rIL-2 protein, IL-2 DNA, or IL-2 synthetic peptides prior to infection with 28 wild-type (wt) HSV-1 strains McKrae and KOS. The critical role of IL-2 is further supported by our data 29 indicating that a single mutation at position T27A in IL-2 completely blocks HSV-1-induced pathology.

Inflammatory infiltration of the trigeminal ganglion after herpes simplex virus type 1 corneal infection

Journal of Virology

Following herpes simplex virus type 1 (HSV-1) infection of the cornea, the virus is transmitted to the trigeminal ganglion, where a brief period of virus replication is followed by establishment of a latent infection in neurons. A possible role of the immune system in regulating virus replication and maintaining latency in the sensory neurons has been suggested. We have investigated the phenotype and cytokine pattern of cells that infiltrate the A/J mouse trigeminal ganglion at various times after HSV-1 corneal infection. HSV antigen expression in the trigeminal ganglion (indicative of the viral lytic cycle) increased until day 3 postinfection (p.i.) and then diminished to undetectable levels by day 7 p.i. The period of declining HSV antigen expression. was associated with a marked increase in Mac-1+ cells. These cells did not appear to coexpress the F4/80+ (macrophage) or the CD8+ (T cell) markers, and none showed polymorphonuclear leukocyte morphology, suggesting a possible early ...

Restrictions that control herpes simplex virus type 1 infection in mouse brain ex vivo

Journal of General Virology, 2011

Elucidating the cellular and molecular factors governing herpes simplex virus type 1 (HSV-1) neurotropism is a prerequisite for understanding HSV-1 encephalitis and for targeting HSV-1-derived vectors for gene transfer to the brain. Earlier we had described anex vivosystem of mouse brain slices and demonstrated a selective and unique infection pattern, mostly around the ventricles. Here, we examined tissue factors controlling HSV-1 infection of brain slices. We demonstrated that heparan sulphate, while an important factor, does not determine the infection pattern. Hyaluronic acid, but not collagen, appears to enhance HSV-1 brain infection. To investigate whether tissue distribution of viral receptors determines the infection pattern, we examined transcription of herpes virus entry mediator and nectin-1 receptor genes in infected and uninfected brain regions. Both the infected and the uninfected regions express the receptors. We also explored the influence of intra-cellular factors. ...

Cytokine-mediated survival from lethal herpes simplex virus infection: role of programmed neuronal death

Proceedings of the National Academy of Sciences, 1995

The mechanisms responsible for cytokinemediated antiviral effects are not fully understood. We approached this problem by studying the outcome of intraocular herpes simplex (HSV) infection in transgenic mice that express interferon y in the photoreceptor cells of the retina. These transgenic mice showed selective survival from lethal HSV-2 infection manifested in both eyes, the optic nerve, and the brain. Although transgenic mice developed greater inflammatory responses to the virus in the eyes, inflammation and viral titers in their brains were equivalent to nontransgenic mice. However, survival of transgenic mice correlated with markedly lower numbers of central neurons undergoing apoptosis. The protooncogene Bcl2 was found to be induced in the HSV-2-infected brains of transgenic mice, allowing us to speculate on its role in fostering neuronal survival in this model. These observations imply a complex interaction between cytokine, virus, and host cellular factors. Our results suggest a cytokine-regulated salvage pathway that allows for survival of infected neurons.