Loss of mandibular lymph node integrity is associated with an increase in sensitivity to HSV-1 infection in CD118-deficient mice.
TL;DR: The adoptive transfer of HSV-specific TCR transgenic CD8+ T cells into CD118−/− mice at the time of infection modestly reduced viral titers in the nervous system suggesting in addition to the generation of HSv-specific CD8 + T cells, other type I IFN-activated pathways are instrumental in controlling acute infection.
Abstract: Type I IFNs are potent antiviral cytokines that contribute to the development of the adaptive immune response. To determine the role of type I IFNs in this process in an infectious disease model, mice deficient in the type I IFN receptor (CD118(-/-)) were ocularly infected with HSV-1 and surveyed at times post infection in the nervous system and lymph node for virus and the host immune response. Virus titers were elevated in the trigeminal ganglia and brain stem with virus disseminating rapidly to the draining lymph node of CD118(-/-) mice. T cell and plasmacytoid dendritic cell infiltration into the brain stem was reduced in CD118(-/-) mice following infection, which correlated with a reduction in CXCL10 but not CXCL9 expression. In contrast, CXCL1 and CCL2 levels were up-regulated in the brainstem of CD118(-/-) mice associated with an increase in F4/80(+) macrophages. By day 5 post infection, there was a significant loss in T, NK, and plasmacytoid dendritic cell numbers in the draining lymph nodes associated with an increase in apoptotic/necrotic T cells and an appreciable lack of HSV-specific CD8(+) T cells. The adoptive transfer of HSV-specific TCR transgenic CD8(+) T cells into CD118(-/-) mice at the time of infection modestly reduced viral titers in the nervous system suggesting in addition to the generation of HSV-specific CD8(+) T cells, other type I IFN-activated pathways are instrumental in controlling acute infection.
Citations
More filters
TL;DR: 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.
127 citations
TL;DR: It is reported that TLR signaling is expendable in herpes simplex virus (HSV)-1 containment as depicted by plaque assays of knockout mice resembling wild-type controls, and an IRF-3-dependent, IRF7- and TLR-independent innate sensor responsible for HSV containment at the site of acute infection is identified.
109 citations
TL;DR: This review illustrates examples of established brain barrier models, in which the specific reaction patterns of different viral families can be analyzed, and highlights the pathogen specific array of cytokines and chemokines involved in immunological responses in viral CNS infections.
Abstract: Neurotropic viruses can cause devastating central nervous system (CNS) infections, especially in young children and the elderly. The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) have been described as relevant sites of entry for specific viruses as well as for leukocytes, which are recruited during the proinflammatory response in the course of CNS infection. In this review, we illustrate examples of established brain barrier models, in which the specific reaction patterns of different viral families can be analyzed. Furthermore, we highlight the pathogen specific array of cytokines and chemokines involved in immunological responses in viral CNS infections. We discuss in detail the link between specific cytokines and chemokines and leukocyte migration profiles. The thorough understanding of the complex and interrelated inflammatory mechanisms as well as identifying universal mediators promoting CNS inflammation is essential for the development of new diagnostic and treatment strategies.
99 citations
Cites background from "Loss of mandibular lymph node integ..."
...In contrast, an increase in macrophages within the CNS of IFNAR-A1 deficient mice has been observed [138]....
[...]
TL;DR: CCL2 expression driven by IFI-16 recognition of HSV-1 facilitates the recruitment of inflammatory monocytes into the cornea proper to control viral replication.
82 citations
TL;DR: Using magnetic resonance imaging and type I IFN receptor–deficient mouse chimeras, it is demonstrated HSV-1 gains access to the murine brain stem and subsequently brain ependymal cells, leading to enlargement of the cerebral lateral ventricle and infection of the brain parenchyma in mice.
Abstract: HSV-1 is the leading cause of sporadic viral encephalitis, with mortality rates approaching 30% despite treatment with the antiviral drug of choice, acyclovir. Permanent neurologic deficits are common in patients that survive, but the mechanism leading to this pathology is poorly understood, impeding clinical advancements in treatment to reduce CNS morbidity. Using magnetic resonance imaging and type I IFN receptor-deficient mouse chimeras, we demonstrate HSV-1 gains access to the murine brain stem and subsequently brain ependymal cells, leading to enlargement of the cerebral lateral ventricle and infection of the brain parenchyma. A similar enlargement in the lateral ventricles is found in a subpopulation of herpes simplex encephalitic patients. Associated with encephalitis is an increase in CXCL1 and CXCL10 levels in the cerebral spinal fluid, TNF-α expression in the ependymal region, and the influx of neutrophils of encephalitic mouse brains. Reduction in lateral ventricle enlargement using anti-secretory factor peptide 16 reduces mortality significantly in HSV-1-infected mice without any effect on expression of inflammatory mediators, infiltration of leukocytes, or changes in viral titer. Microglial cells but not infiltrating leukocytes or other resident glial cells or neurons are the principal source of resistance in the CNS during the first 5 d postinfection through a Toll/IL-1R domain-containing adapter inducing IFN-β-dependent, type I IFN pathway. Our results implicate lateral ventricle enlargement as a major cause of mortality in mice and speculate such an event transpires in a subpopulation of human HSV encephalitic patients.
68 citations
Cites background from "Loss of mandibular lymph node integ..."
...However, analysis of brain cortex and ependyma for cytokine and chemokine (TNF-a and CXCL10) expression by suspension array or leukocyte infiltrate (including neutrophils, macrophages, inflammatory monocytes, and NK cells) by flow cytometry revealed no significant difference in levels or cell numbers comparing peptide- to vehicle-treated mice day 7 to 8 p.i. (data not shown)....
[...]
...We speculate CXCL10 may serve as an easily accessible predictor of inflammation severity in patients with no previous history of neuroinflammatory disease....
[...]
...Likewise, HSE WT mice had detectable levels of IL-1a, CCL2, CXCL1, CXCL9, and CXCL10, with CXCL1 and CXCL10 expression significantly above that recovered in the CSF of non-HSE WT mice day 8 p.i. (Fig....
[...]
...Associated with encephalitis is an increase in CXCL1 and CXCL10 levels in the cerebral spinal fluid, TNF-a expression in the ependymal region, and the influx of neutrophils of encephalitic mouse brains....
[...]
...for CD118 mice) or the relationship between a functional type I IFN pathway and HSV-1–induced CXCL10 (34)....
[...]
References
More filters
TL;DR: Data support a pathogenetic model of HSV infection, in which initial delay in the generation of immune responses to HSV at peripheral sites is mediated by disruption of DC function but is overcome by bystander DC maturation and cross-presentation ofHSV antigens.
Abstract: Several lines of evidence suggest that dendritic cells (DCs), the most potent antigen-presenting cells known, play a role in the immunological control of herpes simplex virus (HSV) infections. HSV infection of DCs induced submaximal maturation, but DCs failed to mature further in response to lipopolysaccharide (LPS). LPS induced interleukin (IL)-12 secretion, and the induction of primary and secondary T cell responses were impaired by infection. Ultimately, DC infection resulted in delayed, asynchronous apoptotic cell death. However, infected DCs induced HSV recall responses in some individuals. Furthermore, soluble factors secreted by DCs after infection induced DC maturation and primed for IL-12 secretion after LPS stimulation. These data support a pathogenetic model of HSV infection, in which initial delay in the generation of immune responses to HSV at peripheral sites is mediated by disruption of DC function but is overcome by bystander DC maturation and cross-presentation of HSV antigens.
123 citations
TL;DR: Different effects of type I and II IFNs in limiting systemic dissemination of HSV-1 are demonstrated and the use of bioluminescence imaging for studies of viral pathogenesis is validated.
Abstract: Herpes simplex virus type 1 (HSV-1) can produce disseminated, systemic infection in neonates and patients with AIDS or other immunocompromising diseases, resulting in significant morbidity and mortality in spite of antiviral therapy. Components of host immunity that normally limit HSV-1 to localized epithelial and neuronal infection remain incompletely defined. We used in vivo bioluminescence imaging to determine effects of type I and II interferons (IFNs) on replication and tropism of HSV-1 infection in mice with genetic deficiency of type I, type II, or both type I and II IFN receptors. Following footpad or ocular infection of mice lacking type I IFN receptors, HSV-1 spread to parenchymal organs, including lung, liver, spleen, and regional lymph nodes, but mice survived. Deletion of type I and II IFN receptors produced quantitatively greatest and most widespread dissemination of virus to visceral organs and the nervous system, and these mice invariably died after ocular or footpad infection. Type II receptor knockout and wild-type mice had comparable viral replication and localization, with no systemic spread of HSV-1 or lethality. Therefore, while isolated deficiency of type II IFN receptors did not affect pathogenesis, loss of these receptors in combination with genetic deletion of type I receptors had a profound effect on susceptibility to HSV-1. These data demonstrate different effects of type I and II IFNs in limiting systemic dissemination of HSV-1 and further validate the use of bioluminescence imaging for studies of viral pathogenesis.
119 citations
"Loss of mandibular lymph node integ..." refers methods in this paper
...A previous study reported the dissemination of HSV-1 in CD118 / mice following inoculation of mice in the footpad or cornea using a luciferase-engineered recombinant virus and bioluminescence imaging (28)....
[...]
...Previous investigations have used CD118-deficient (CD118 / ) mice to demonstrate the sensitivity of these animals to HSV-1 infection based on virus replication, dissemination of the virus in the host, or to illustration of the importance of virally encoded proteins (6, 27, 28)....
[...]
Journal Article•
TL;DR: It is difficult to rule out the possibility that the presence of HSV2 or of antigens is not an independent event unrelated to the cancer, and it is possible that frequent or constant antigenic stimulation occurs in at least some cases of recurrent herpetic infections.
Abstract: Herpes-simplex virus 1 (HSV1) and 2 can cause recurrent infection in man and in nonhuman species localized on a specific area of the body such as face cornea or genitals. The origin of the virus responsible for a recurrent infection is not usually apparent. Some possible sources of virus can be exogenous infection endogenous infection from another site of the body chronic continuous viral multiplication around the site of involvement and persistence of the virus at the site of the recurrent infection. No definite information is yet available regarding the mechanism by which HSV1 or HSV2 persists and it is triggered to multiply or regarding the cells that harbor the virus. It is possible that frequent or constant antigenic stimulation occurs in at least some cases of recurrent herpetic infections. The role of antibodies and of interferon in host resistance to HSV remains to be elucidated. Several recent studies have shown the association of more than a dozen herpes viruses with cancer in man and various animals; for example with limphoma and with squamous cell carcinoma of the lip and cancer of the cervix. Genital HSV infections and cervical cancer were first linked when it was noted that women with genital herpes had a high frequency of cervical dysplasia and cancer. The results of new seroepidemiologic studies on this subject are still difficult to evaluate. Inocculation of HSV2 in laboratory animals has resulted in sarcomas but it has never been possible to prove that the virus caused the tumors since no HSV antigens could be detected in the tumors. However herpesvirus antigens have been demonstrated by immunofluorescent technics in exfoliated cervical cells obtained from women with dysplasia carcinoma in situ and invasive carcinoma. In the absence of other kinds of data it is difficult to rule out the possibility that the presence of HSV2 or of antigens is not an independent event unrelated to the cancer.
118 citations
"Loss of mandibular lymph node integ..." refers background in this paper
...Unlike beta- and gamma-herpesviruses, it was originally thought primary HSV-1 infection does not cause viremia in healthy patients (66, 67)....
[...]
TL;DR: It is concluded that fatal HSE in 129 mice results from widespread damage in the brain stem caused by destructive inflammatory responses initiated early in infection by massive infiltration of innate cells.
Abstract: This study was undertaken to investigate possible immune mechanisms in fatal herpes simplex virus type 1 (HSV-1) encephalitis (HSE) after HSV-1 corneal inoculation. Susceptible 129S6 (129) but not resistant C57BL/6 (B6) mice developed intense focal inflammatory brain stem lesions of primarily F4/80(+) macrophages and Gr-1(+) neutrophils detectable by magnetic resonance imaging as early as day 6 postinfection (p.i.). Depletion of macrophages and neutrophils significantly enhanced the survival of infected 129 mice. Immunodeficient B6 (IL-7R(-/-) Kit(w41/w41)) mice lacking adaptive cells (B6-E mice) and transplanted with 129 bone marrow showed significantly accelerated fatal HSE compared to B6-E mice transplanted with B6 marrow or control nontransplanted B6-E mice. In contrast, there was no difference in ocular viral shedding in B6-E mice transplanted with 129 or B6 bone marrow. Acyclovir treatment of 129 mice beginning on day 4 p.i. (24 h after HSV-1 first reaches the brain stem) reduced nervous system viral titers to undetectable levels but did not alter brain stem inflammation or mortality. We conclude that fatal HSE in 129 mice results from widespread damage in the brain stem caused by destructive inflammatory responses initiated early in infection by massive infiltration of innate cells.
116 citations
"Loss of mandibular lymph node integ..." refers background in this paper
..., which is likely due to the inflammatory response elicited by the pathogen including cytokines and proteases emanating from tissue macrophages and neutrophils that infiltrate the brain following infection (53)....
[...]
TL;DR: ICP0's function as a viral IFN antagonist is necessary in vivo to prevent an innate, Stat 1-dependent host response from rapidly repressing productive HSV-1 replication.
Abstract: The herpes simplex virus type 1 (HSV-1) ICP0 protein is an E3 ubiquitin ligase, which is encoded within the HSV-1 latency-associated locus. When ICP0 is not synthesized, the HSV-1 genome is acutely susceptible to cellular repression. Reciprocally, when ICP0 is synthesized, viral replication is efficiently initiated from virions or latent HSV-1 genomes. The current study was initiated to determine if ICP0's putative role as a viral interferon (IFN) antagonist may be relevant to the process by which ICP0 influences the balance between productive replication versus cellular repression of HSV-1. Wild-type (ICP0+) strains of HSV-1 produced lethal infections in scid or rag2-/- mice. The replication of ICP0- null viruses was rapidly repressed by the innate host response of scid or rag2-/- mice, and the infected animals remained healthy for months. In contrast, rag2-/- mice that lacked the IFN-α/β receptor (rag2-/- ifnar-/-) or Stat 1 (rag2-/- stat1-/-) failed to repress ICP0- viral replication, resulting in uncontrolled viral spread and death. Thus, the replication of ICP0- viruses is potently repressed in vivo by an innate immune response that is dependent on the IFN-α/β receptor and the downstream transcription factor, Stat 1. ICP0's function as a viral IFN antagonist is necessary in vivo to prevent an innate, Stat 1-dependent host response from rapidly repressing productive HSV-1 replication. This antagonistic relationship between ICP0 and the host IFN response may be relevant in regulating whether the HSV-1 genome is expressed, or silenced, in virus-infected cells in vivo. These results may also be clinically relevant. IFN-sensitive ICP0- viruses are avirulent, establish long-term latent infections, and induce an adaptive immune response that is highly protective against lethal challenge with HSV-1. Therefore, ICP0- viruses appear to possess the desired safety and efficacy profile of a live vaccine against herpetic disease.
110 citations
"Loss of mandibular lymph node integ..." refers background or methods in this paper
...Relative to HSV-1 infection, STAT1-deficient mice are profoundly sensitive to infection underscored by avirulent HSV-1 mutants that replicate and spread in STAT1-deficient animals but not in fully competent wild type (WT)(3) mice (6)....
[...]
...Previous investigations have used CD118-deficient (CD118 / ) mice to demonstrate the sensitivity of these animals to HSV-1 infection based on virus replication, dissemination of the virus in the host, or to illustration of the importance of virally encoded proteins (6, 27, 28)....
[...]