scholarly journals Role Played by Receptors for Advanced Glycosylation End Products in Corneal Endothelial Cells after HSV-1 Infection

2021 ◽  
Vol 22 (11) ◽  
pp. 5833
Author(s):  
Dai Miyazaki ◽  
Michiko Kandori-Inoue ◽  
Yumiko Shimizu ◽  
Fumie Ohtani ◽  
Ikuyo Chono ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Corneal Endothelial Cells ◽  
Interferon Β ◽  
Cpg Dna ◽  
Amyloid A ◽  
End Products ◽  
Hsv 1

Senescence, sterile inflammation, and infection cause dysfunction of corneal endothelial cells, leading to visual morbidity that may require corneal transplantation. With increasing age, the extracellular matrix is modified by non-enzymatic glycation forming advanced glycation end products (AGEs). The modifications are primarily sensed by the receptors for the AGEs (RAGE) and are manifested as a type I interferon response. Interestingly, in our study, human corneal endothelial cells (HCEn) cells did not respond to the typical RAGE ligands, including the AGEs, high mobility group box 1 (HMGB1), and serum amyloid-A (SAA). Instead, HCEn cells responded exclusively to the CpG DNA, which is possessed by typical corneal pathogen, herpes simplex virus-1 (HSV-1). Upon HSV-1 infection, the surface expression of RAGE was increased, and endocytosed HSV-1 was associated with RAGE and CpG DNA receptor, TLR9. RAGE DNA transfection markedly increased interferon-β secretion by CpG DNA or HSV-1 infection. HSV-1 infection-induced interferon-β secretion was abolished by TLR9 inhibition and partially by RAGE inhibition. Global transcriptional response analysis confirmed that RAGE and TLR9 were both significantly involved in type I interferon responses. We conclude that RAGE is a sensor of HSV-1 infection and provokes a type I interferon response.

scholarly journals The Type I Interferon Response Determines Differences in Choroid Plexus Susceptibility between Newborns and Adults in Herpes Simplex Virus Encephalitis

mBio ◽  
2016 ◽  
Vol 7 (2) ◽  
Author(s):  
Douglas R. Wilcox ◽  
Stephen S. Folmsbee ◽  
William J. Muller ◽  
Richard Longnecker
Keyword(s):  
Choroid Plexus ◽  
Type I Interferon ◽  
Adult Brain ◽  
Interferon Response ◽  
Type I ◽  
Β Receptor ◽  
Simplex Virus ◽  
The Brain ◽  
Hsv 1

ABSTRACTNewborns are significantly more susceptible to severe viral encephalitis than adults, with differences in the host response to infection implicated as a major factor. However, the specific host signaling pathways responsible for differences in susceptibility and neurologic morbidity have remained unknown. In a murine model of HSV encephalitis, we demonstrated that the choroid plexus (CP) is susceptible to herpes simplex virus 1 (HSV-1) early in infection of the newborn but not the adult brain. We confirmed susceptibility of the CP to HSV infection in a human case of newborn HSV encephalitis. We investigated components of the type I interferon (IFN) response in the murine brain that might account for differences in cell susceptibility and found that newborns have a dampened interferon response and significantly lower basal levels of the alpha/beta interferon (IFN-α/β) receptor (IFNAR) than do adults. To test the contribution of IFNAR to restricting infection from the CP, we infected IFNAR knockout (KO) adult mice, which showed restored CP susceptibility to HSV-1 infection in the adult. Furthermore, reduced IFNAR levels did not account for differences we found in the basal levels of several other innate signaling proteins in the wild-type newborn and the adult, including protein kinase R (PKR), that suggested specific regulation of innate immunity in the developing brain. Viral targeting of the CP, a region of the brain that plays a critical role in neurodevelopment, provides a link between newborn susceptibility to HSV and long-term neurologic morbidity among survivors of newborn HSV encephalitis.IMPORTANCECompared to adults, newborns are significantly more susceptible to severe disease following HSV infection. Over half of newborn HSV infections result in disseminated disease or encephalitis, with long-term neurologic morbidity in 2/3 of encephalitis survivors. We investigated differences in host cell susceptibility between newborns and adults that contribute to severe central nervous system disease in the newborn. We found that, unlike the adult brain, the newborn choroid plexus (CP) was susceptible early in HSV-1 infection. We demonstrated that IFN-α/β receptor levels are lower in the newborn brain than in the adult brain and that deletion of this receptor restores susceptibility of the CP in the adult brain. The CP serves as a barrier between the blood and the cerebrospinal fluid and plays a role in proper neurodevelopment. Susceptibility of the newborn choroid plexus to HSV-1 has important implications in viral spread to the brain and, also, in the neurologic morbidity following HSV encephalitis.

scholarly journals Comprehensive Mutagenesis of Herpes Simplex Virus 1 Genome Identifies UL42 as an Inhibitor of Type I Interferon Induction

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Maxime Chapon ◽  
Kislay Parvatiyar ◽  
Saba Roghiyh Aliyari ◽  
Jeffrey S. Zhao ◽  
Genhong Cheng
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
High Throughput ◽  
Type I Interferon ◽  
Viral Proteins ◽  
Interferon Response ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT In spite of several decades of research focused on understanding the biology of human herpes simplex virus 1 (HSV-1), no tool has been developed to study its genome in a high-throughput fashion. Here, we describe the creation of a transposon insertion mutant library of the HSV-1 genome. Using this tool, we aimed to identify novel viral regulators of type I interferon (IFN-I). HSV-1 evades the host immune system by encoding viral proteins that inhibit the type I interferon response. Applying differential selective pressure, we identified the three strongest viral IFN-I regulators in HSV-1. We report that the viral polymerase processivity factor UL42 interacts with the host transcription factor IFN regulatory factor 3 (IRF-3), inhibiting its phosphorylation and downstream beta interferon (IFN-β) gene transcription. This study represents a proof of concept for the use of high-throughput screening of the HSV-1 genome in investigating viral biology and offers new targets both for antiviral therapy and for oncolytic vector design. IMPORTANCE This work is the first to report the use of a high-throughput mutagenesis method to study the genome of HSV-1. We report three novel viral proteins potentially involved in regulating the host type I interferon response. We describe a novel mechanism by which the viral protein UL42 is able to suppress the production of beta interferon. The tool we introduce in this study can be used to study the HSV-1 genome in great detail to better understand viral gene functions.

scholarly journals HSV-1 Targets Lymphatic Vessels in the Eye and Draining Lymph Node of Mice Leading to Edema in the Absence of a Functional Type I Interferon Response

2013 ◽  
Vol 183 (4) ◽  
pp. 1233-1242 ◽  
Author(s):  
Katie M. Bryant-Hudson ◽  
Ana J. Chucair-Elliott ◽  
Christopher D. Conrady ◽  
Alex Cohen ◽  
Min Zheng ◽  
...  
Keyword(s):  
Lymph Node ◽  
Type I Interferon ◽  
Lymphatic Vessels ◽  
Interferon Response ◽  
Type I ◽  
Functional Type ◽  
Draining Lymph Node ◽  
Hsv 1

scholarly journals ALG2 regulates type I interferon responses by inhibiting STING trafficking

2021 ◽  
Author(s):  
Wangsheng Ji ◽  
Lianfei Zhang ◽  
Xiaoyu Xu ◽  
Xinqi Liu
Keyword(s):  
Immune Responses ◽  
Type I Interferon ◽  
Innate Immune ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Innate Immune Responses ◽  
Downstream Signaling ◽  
Interferon Responses ◽  
Hsv 1

Stimulator of IFN genes (STING), an endoplasmic reticulum (ER) signaling adaptor, is essential for the type I interferon response to cytosolic dsDNA. The translocation from the ER to perinuclear vesicles following binding cGAMP is a critical step for STING to activate downstream signaling molecules, which lead to the production of interferon and pro-inflammatory cytokines. Here we found that apoptosis-linked gene 2 (ALG2) suppressed STING signaling induced by either HSV-1 infection or cGAMP presence. Knockout of ALG2 markedly facilitated the expression of type I interferons upon cGAMP treatment or HSV-1 infection in THP-1 monocytes. Mechanistically, ALG2 associated with the C-terminal tail (CTT) of STING and inhibited its trafficking from ER to perinuclear region. Furthermore, the ability of ALG2 to coordinate calcium was crucial for its regulation of STING trafficking and DNA-induced innate immune responses. This work suggests that ALG2 is involved in DNA-induced innate immune responses by regulating STING trafficking.

scholarly journals Testicular Degeneration and Infertility following Arbovirus Infection

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Giantonella Puggioni ◽  
Davide Pintus ◽  
Eleonora Melzi ◽  
Giorgio Meloni ◽  
Angela Maria Rocchigiani ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sertoli Cells ◽  
Reproductive Tract ◽  
Type I Interferon ◽  
Clinical Signs ◽  
Interferon Response ◽  
Type I ◽  
Male Reproductive Tract ◽  
Testicular Lesions ◽  
Testicular Degeneration

ABSTRACTArboviruses can cause a variety of clinical signs, including febrile illness, arthritis, encephalitis, and hemorrhagic fever. The recent Zika epidemic highlighted the possibility that arboviruses may also negatively affect the male reproductive tract. In this study, we focused on bluetongue virus (BTV), the causative agent of bluetongue and one of the major arboviruses of ruminants. We show that rams that recovered from bluetongue displayed signs of testicular degeneration and azoospermia up to 100 days after the initial infection. Importantly, testicular degeneration was induced in rams experimentally infected with either a high (BTV-1IT2006)- or a low (BTV-1IT2013)-virulence strain of BTV. Rams infected with the low-virulence BTV strain displayed testicular lesions in the absence of other major clinical signs. Testicular lesions in BTV-infected rams were due to viral replication in the endothelial cells of the peritubular areas of the testes, resulting in stimulation of a type I interferon response, reduction of testosterone biosynthesis by Leydig cells and destruction of Sertoli cells and the blood-testis barrier in more severe cases. Hence, BTV induces testicular degeneration and disruption of spermatogenesis by replicating solely in the endothelial cells of the peritubular areas unlike other gonadotropic viruses. This study shows that a naturally occurring arboviral disease can cause testicular degeneration and affect male fertility at least temporarily.IMPORTANCEDuring the recent Zika epidemic, it has become apparent that arboviruses could potentially cause reproductive health problems in male patients. Little is known regarding the effects that arboviruses have on the male reproductive tract. Here, we studied bluetongue virus (BTV), an arbovirus of ruminants, and its effects on the testes of rams. We show that BTV was able to induce testicular degeneration in naturally and experimentally infected rams. Testicular degeneration was caused by BTV replication in the endothelial cells of the peritubular area surrounding the seminiferous tubules (the functional unit of the testes) and was associated with a localized type I interferon response, destruction of the cells supporting the developing germinal cells (Sertoli cells), and reduction of testosterone synthesis. As a result of BTV infection, rams became azoospermic. This study highlights that problems in the male reproductive tract caused by arboviruses could be more common than previously thought.

scholarly journals Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3

2018 ◽  
Author(s):  
Chao Qin ◽  
Rui Zhang ◽  
Yue Lang ◽  
Anwen Shao ◽  
Aotian Xu ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Pseudorabies Virus ◽  
Viral Infections ◽  
Type I Interferon ◽  
Interferon Response ◽  
Interferon Α ◽  
Type I ◽  
Viral Inhibition ◽  
Simplex Virus ◽  
Hsv 1

AbstractType I interferon response plays a prominent role against viral infection, which is frequently disrupted by viruses. Here, we report Bcl-2 associated transcription factor 1 (Bclaf1) is degraded during the alphaherpesvirus Pseudorabies virus (PRV) and Herpes simplex virus type 1 (HSV-1) infections through the viral protein US3. We further reveal that Bclaf1 functions critically in type I interferon signaling. Knockdown or knockout of Bclaf1 in cells significantly impairs interferon-α (IFNα)-mediated gene transcription and viral inhibition against US3 deficient PRV and HSV-1. Mechanistically, Bclaf1 maintains a mechanism allowing STAT1 and STAT2 to be efficiently phosphorylated in response to IFNα, and more importantly, facilitates IFN-stimulated gene factor 3 (ISGF3) binding with IFN-stimulated response elements (ISRE) for efficient gene transcription by directly interacting with ISRE and STAT2. Our studies establish the importance of Bclaf1 in IFNα-induced antiviral immunity and in the control of viral infections.

Viral Invasion and Type I Interferon Response Characterize the Immunophenotypes during COVID-19 Infection

2020 ◽  
Author(s):  
Lai Wei ◽  
Siqi Ming ◽  
Bin Zou ◽  
Yongjian Wu ◽  
Zhongsi Hong ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Interferon Response ◽  
Type I

scholarly journals Positive natural selection in primate genes of the type I interferon response

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Elena N. Judd ◽  
Alison R. Gilchrist ◽  
Nicholas R. Meyerson ◽  
Sara L. Sawyer
Keyword(s):  
Natural Selection ◽  
Positive Selection ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Multiple Sequence Alignments ◽  
Interferon Stimulated Genes ◽  
Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

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