scholarly journals Endogenous Retroviruses Provide Protection Against Vaginal HSV-2 Disease

2022 ◽  
Vol 12 ◽  
Author(s):  
Radeesha Jayewickreme ◽  
Tianyang Mao ◽  
William Philbrick ◽  
Yong Kong ◽  
Rebecca S. Treger ◽  
...  
Keyword(s):  
Leukemia Virus ◽  
Endogenous Retroviruses ◽  
Protective Mechanism ◽  
Type I ◽  
Toll Like Receptor ◽  
Matrix Organization ◽  
Simplex Virus ◽  
Deficient Mice ◽  
Eukaryotic Genomes

Endogenous retroviruses (ERVs) are genomic sequences that originated from retroviruses and are present in most eukaryotic genomes. Both beneficial and detrimental functions are attributed to ERVs, but whether ERVs contribute to antiviral immunity is not well understood. Here, we used herpes simplex virus type 2 (HSV-2) infection as a model and found that Toll-like receptor 7 (Tlr7-/-) deficient mice that have high systemic levels of infectious ERVs are protected from intravaginal HSV-2 infection and disease, compared to wildtype C57BL/6 mice. We deleted the endogenous ecotropic murine leukemia virus (Emv2) locus on the Tlr7-/- background (Emv2-/-Tlr7-/-) and found that Emv2-/-Tlr7-/- mice lose protection against HSV-2 infection. Intravaginal application of purified ERVs from Tlr7-/- mice prior to HSV-2 infection delays disease in both wildtype and highly susceptible interferon-alpha receptor-deficient (Ifnar1-/-) mice. However, intravaginal ERV treatment did not protect Emv2-/-Tlr7-/- mice from HSV-2 disease, suggesting that the protective mechanism mediated by exogenous ERV treatment may differ from that of constitutively and systemically expressed ERVs in Tlr7-/- mice. We did not observe enhanced type I interferon (IFN-I) signaling in the vaginal tissues from Tlr7-/- mice, and instead found enrichment in genes associated with extracellular matrix organization. Together, our results revealed that constitutive and/or systemic expression of ERVs protect mice against vaginal HSV-2 infection and delay disease.

scholarly journals Type I Interferon Production during Herpes Simplex Virus Infection Is Controlled by Cell-Type-Specific Viral Recognition through Toll-Like Receptor 9, the Mitochondrial Antiviral Signaling Protein Pathway, and Novel Recognition Systems

2007 ◽  
Vol 81 (24) ◽  
pp. 13315-13324 ◽  
Author(s):  
Simon B. Rasmussen ◽  
Louise N. Sørensen ◽  
Lene Malmgaard ◽  
Nina Ank ◽  
Joel D. Baines ◽  
...  
Keyword(s):  
Viral Entry ◽  
Type I Interferon ◽  
Type I ◽  
Toll Like Receptor ◽  
Cell Type ◽  
Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling ◽  
Simplex Virus ◽  
Mitochondrial Antiviral Signaling Protein

ABSTRACT Recognition of viruses by germ line-encoded pattern recognition receptors of the innate immune system is essential for rapid production of type I interferon (IFN) and early antiviral defense. We investigated the mechanisms of viral recognition governing production of type I IFN during herpes simplex virus (HSV) infection. We show that early production of IFN in vivo is mediated through Toll-like receptor 9 (TLR9) and plasmacytoid dendritic cells, whereas the subsequent alpha/beta IFN (IFN-α/β) response is derived from several cell types and induced independently of TLR9. In conventional DCs, the IFN response occurred independently of viral replication but was dependent on viral entry. Moreover, using a HSV-1 UL15 mutant, which fails to package viral DNA into the virion, we found that entry-dependent IFN induction also required the presence of viral genomic DNA. In macrophages and fibroblasts, where the virus was able to replicate, HSV-induced IFN-α/β production was dependent on both viral entry and replication, and ablated in cells unable to signal through the mitochondrial antiviral signaling protein pathway. Thus, during an HSV infection in vivo, multiple mechanisms of pathogen recognition are active, which operate in cell-type- and time-dependent manners to trigger expression of type I IFN and coordinate the antiviral response.

scholarly journals Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

2019 ◽  
Author(s):  
Paul Dembny ◽  
Andrew G. Newman ◽  
Manvendra Singh ◽  
Michael Hinz ◽  
Michal Szczepek ◽  
...  
Keyword(s):  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Endogenous Ligand ◽  
Human Endogenous Retroviruses ◽  
Retroviral Transcripts ◽  
The Brain ◽  
Deficient Mice

AbstractAlthough human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs have been suggested to be involved in neurological disorders, little is known about their biological function and pathophysiological relevance. HERV-K(HML-2) comprises evolutionarily young proviruses transcribed in the brain. We report that RNA derived from an HERV-K(HML-2) env gene region binds to the human RNA-sensing Toll-like receptor (TLR) 8, activates human TLR8, as well as murine Tlr7, and causes neurodegeneration through TLR8 and Tlr7 in neurons and microglia. HERV-K(HML-2) RNA introduced extracellularly into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimer’s disease (AD), resulted in neurodegeneration. Tlr7-deficient mice were protected against neurodegenerative effects, but were re-sensitized towards HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Accordingly, transcriptome datasets of human brain samples from AD patients revealed a specific correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from AD individuals compared to controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for human TLR8 and murine Tlr7 and imply a functional contribution of specific human endogenous retroviral transcripts to neurodegenerative processes such as AD.

scholarly journals Toll-like receptor 7 suppresses virus replication in neurons but does not affect viral pathogenesis in a mouse model of Langat virus infection

2013 ◽  
Vol 94 (2) ◽  
pp. 336-347 ◽  
Author(s):  
David G. Baker ◽  
Tyson A. Woods ◽  
Niranjan B. Butchi ◽  
Timothy M. Morgan ◽  
R. Travis Taylor ◽  
...  
Keyword(s):  
Virus Infection ◽  
Virus Replication ◽  
Type I ◽  
Toll Like Receptor ◽  
Virus Infections ◽  
Ssrna Virus ◽  
Langat Virus ◽  
The Central Nervous System ◽  
Interferon Responses ◽  
Deficient Mice

Toll-like receptor 7 (TLR7) recognizes guanidine-rich viral ssRNA and is an important mediator of peripheral immune responses to several ssRNA viruses. However, the role that TLR7 plays in regulating the innate immune response to ssRNA virus infections in specific organs such as the central nervous system (CNS) is not as clear. This study examined the influence of TLR7 on the neurovirulence of Langat virus (LGTV), a ssRNA tick-borne flavivirus. TLR7 deficiency did not substantially alter the onset or incidence of LGTV-induced clinical disease; however, it did significantly affect virus levels in the CNS with a log10 increase in virus titres in brain tissue from TLR7-deficient mice. This difference in virus load was also observed following intracranial inoculation, indicating a direct effect of TLR7 deficiency on regulating virus replication in the brain. LGTV-induced type I interferon responses in the CNS were not dependent on TLR7, being higher in TLR7-deficient mice compared with wild-type controls. In contrast, induction of pro-inflammatory cytokines including tumour necrosis factor, CCL3, CCL4 and CXCL13 were dependent on TLR7. Thus, although TLR7 is not essential in controlling LGTV pathogenesis, it is important in controlling virus infection in neurons in the CNS, possibly by regulating neuroinflammatory responses.

DIFFERENCE BETWEEN HERPES SIMPLEX VIRUS TYPE I AND TYPE 2 NEONATAL ENCEPHALITIS IN NEUROLOGICAL OUTCOME

The Lancet ◽  
1988 ◽  
Vol 331 (8575-8576) ◽  
pp. 1-4 ◽  
Author(s):  
Lawrence Corey ◽  
E.Franklin Stone ◽  
RichardJ. Whitley ◽  
Kathleen Mohan
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Neurological Outcome ◽  
Type I ◽  
Simplex Virus

scholarly journals Memory-Type CD8+T Cells Protect IL-2 Receptor α-Deficient Mice from Systemic Infection with Herpes Simplex Virus Type 2

2000 ◽  
Vol 165 (8) ◽  
pp. 4552-4560 ◽  
Author(s):  
Hironaka Tsunobuchi ◽  
Hitoshi Nishimura ◽  
Fumi Goshima ◽  
Tohru Daikoku ◽  
Yukihiro Nishiyama ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cd8 T Cells ◽  
Herpes Simplex Virus Type ◽  
Systemic Infection ◽  
Memory Type ◽  
Simplex Virus ◽  
Deficient Mice

scholarly journals Toll-like Receptor 9–mediated Recognition of Herpes Simplex Virus-2 by Plasmacytoid Dendritic Cells

2003 ◽  
Vol 198 (3) ◽  
pp. 513-520 ◽  
Author(s):  
Jennifer Lund ◽  
Ayuko Sato ◽  
Shizuo Akira ◽  
Ruslan Medzhitov ◽  
Akiko Iwasaki
Keyword(s):  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Plasmacytoid Dendritic Cells ◽  
Endocytic Pathway ◽  
Type I ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

Plasmacytoid dendritic cells (pDCs) have been identified as a potent secretor of the type I interferons (IFNs) in response to CpG as well as several viruses. In this study, we examined the molecular mechanism of virus recognition by pDCs. First, we demonstrated that the CD11c+Gr-1intB220+ pDCs from mouse bone marrow secreted high levels of IFN-α in response to either live or UV-inactivated Herpes simplex virus-2 (HSV-2). Next, we identified that IFN-α secretion by pDCs required the expression of the adaptor molecule MyD88, suggesting the involvement of a Toll-like receptor (TLR) in HSV-2 recognition. To test whether a TLR mediates HSV-2–induced IFN-α secretion from pDCs, various knockout mice were examined. These experiments revealed a clear requirement for TLR9 in this process. Further, we demonstrated that purified HSV-2 DNA can trigger IFN-α secretion from pDCs and that inhibitory CpG oligonucleotide treatment diminished HSV-induced IFN-α secretion by pDCs in a dose-dependent manner. The recognition of HSV-2 by TLR9 was mediated through an endocytic pathway that was inhibited by chloroquine or bafilomycin A1. The strict requirement for TLR9 in IFN-α secretion was further confirmed by the inoculation of HSV-2 in vivo. Therefore, these results demonstrate a novel mechanism whereby the genomic DNA of a virus can engage TLR9 and result in the secretion of IFN-α by pDCs.

scholarly journals Induction of Innate Immunity against Herpes Simplex Virus Type 2 Infection via Local Delivery of Toll-Like Receptor Ligands Correlates with Beta Interferon Production

2006 ◽  
Vol 80 (20) ◽  
pp. 9943-9950 ◽  
Author(s):  
Navkiran Gill ◽  
Philip M. Deacon ◽  
Brian Lichty ◽  
Karen L. Mossman ◽  
Ali A. Ashkar
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Genital Tract ◽  
Local Delivery ◽  
Poly I:C ◽  
Type I ◽  
Tnf Α ◽  
Ifn Γ ◽  
Simplex Virus

ABSTRACT Toll-like receptors (TLRs) constitute a family of innate receptors that recognize and respond to a wide spectrum of microorganisms, including fungi, bacteria, viruses, and protozoa. Previous studies have demonstrated that ligands for TLR3 and TLR9 induce potent innate antiviral responses against herpes simplex virus type 2 (HSV-2). However, the factor(s) involved in this innate protection is not well-defined. Here we report that production of beta interferon (IFN-β) but not production of IFN-α, IFN-γ, or tumor necrosis factor alpha (TNF-α) strongly correlates with innate protection against HSV-2. Local delivery of poly(I:C) and CpG oligodeoxynucleotides induced significant production of IFN-β in the genital tract and provided complete protection against intravaginal (IVAG) HSV-2 challenge. There was no detectable IFN-β in mice treated with ligands for TLR4 or TLR2, and these mice were not protected against subsequent IVAG HSV-2 challenge. There was no correlation between levels of TNF-α or IFN-γ in the genital tract and protection against IVAG HSV-2 challenge following TLR ligand delivery. Both TNF-α−/− and IFN-γ−/− mice were protected against IVAG HSV-2 challenge following local delivery of poly(I:C). To confirm that type I interferon, particularly IFN-β, mediates innate protection, mice unresponsive to type I interferons (IFN-α/βR−/− mice) and mice lacking IFN regulatory factor-3 (IRF-3−/− mice) were treated with poly(I:C) and then challenged with IVAG HSV-2. There was no protection against HSV-2 infection following poly(I:C) treatment of IFN-α/βR−/− or IRF-3−/− mice. Local delivery of murine recombinant IFN-β protected C57BL/6 and IRF-3−/− mice against IVAG HSV-2 challenge. Results from these in vivo studies clearly suggest a strong correlation between IFN-β production and innate antiviral immunity against HSV-2.

Cell-Type-SpecificTrans-Activation of Herpes Simplex Virus Thymidine Kinase Promoter by the Human T-Cell Leukemia Virus Type I Tax Protein

2001 ◽  
Vol 20 (9) ◽  
pp. 563-568 ◽  
Author(s):  
Satoshi Kubota ◽  
Yoshiki Mukudai ◽  
Takako Hattori ◽  
Takanori Eguchi ◽  
Seiji Kondo ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Leukemia Virus ◽  
Type I ◽  
Cell Leukemia ◽  
Cell Type ◽  
Cell Leukemia Virus Type ◽  
Tax Protein ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Simplex Virus
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