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Arthritis Research & Therapy Jul 2023To compare infectious risk between JAK inhibitors (JAKis) versus TNF inhibitors (TNFis) among rheumatoid arthritis (RA) patients in Korea. (Comparative Study)
Comparative Study
BACKGROUND
To compare infectious risk between JAK inhibitors (JAKis) versus TNF inhibitors (TNFis) among rheumatoid arthritis (RA) patients in Korea.
METHODS
Using 2009-2019 Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating a JAKi or TNFi. The primary outcomes were herpes zoster (HZ), serious bacterial (SBI), and opportunistic infections (OI). Propensity-score fine-stratification (PSS) and weighting were applied to adjust for > 70 baseline covariates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing JAKi versus TNFi users.
RESULTS
We included 2963 JAKi initiators PSS-weighted on 5169 TNFi initiators. During a follow-up of 1.16 years, the most frequent type of infections was HZ with incidence rate (IR) per 100 person-years of 11.54 and 4.88 in JAKi and TNFi users, respectively. The IR of SBI was 1.39 and 1.32, respectively. The OI was rare with a majority being tuberculosis and showed an IR of 0.11 and 0.49 in JAKi and TNFi users, respectively. The PSS-weighted HR (95% CI) for individual types of infections was 2.37 (2.00-2.80) for HZ, 1.04 (0.71-1.52) for SBI, and 0.25 (0.09-0.73) for OI.
CONCLUSIONS
This population-based cohort study on RA patients treated with JAKi or TNFi in Korea showed an exceptionally high IR of HZ in both treatment groups compared to that from Western countries, with an approximately doubled risk associated with JAKi versus TNFi use. The risk of SBI was comparable, but the risk of OI, particularly tuberculosis, was less among JAKi than TNFi initiators.
Topics: Humans; Antirheumatic Agents; Arthritis, Rheumatoid; Cohort Studies; Herpes Zoster; Herpesvirus 3, Human; Janus Kinase Inhibitors; Opportunistic Infections; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha
PubMed: 37495973
DOI: 10.1186/s13075-023-03111-w -
PLoS Pathogens Jul 2023Deubiquitinating enzymes (DUBs) regulate antiviral immune response through targeting DNA sensor signaling pathway members. As one of the DNA sensors, interferon (IFN)-γ...
Deubiquitinating enzymes (DUBs) regulate antiviral immune response through targeting DNA sensor signaling pathway members. As one of the DNA sensors, interferon (IFN)-γ inducible protein 16 (IFI16) play a major role in response to virus infections through activating the canonical STING/TBK-1/IRF3 signaling pathway. Only a few studies discuss the function of DUBs in IFI16-mediated antiviral response. Ubiquitin-specific protease 12 (USP12), which is one of the major members of the USP family, participates in various biological functions. However, whether USP12 regulates the nucleic acid sensor to modulate antiviral immune responses has not yet been elucidated. In this study, we found that knockout or knockdown of USP12 impaired the HSV-1-induced expressions of IFN-β, CCL-5, IL-6, and downstream interferon-stimulated genes (ISGs). Moreover, USP12 deficiency increased HSV-1 replication and host susceptibility to HSV-1 infection. Mechanistically, USP12 inhibited the proteasome-dependent degradation of IFI16 through its deubiquitinase activity, thereby maintaining IFI16 stability and promoting IFI16-STING-IRF3- and p65-mediated antiviral signaling. Overall, our findings demonstrate an essential role of USP12 in DNA-sensing signaling and contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses.
Topics: Humans; Phosphoproteins; Herpesvirus 1, Human; Herpes Simplex; Interferons; Antiviral Agents; Immunity, Innate; Ubiquitin Thiolesterase; Nuclear Proteins
PubMed: 37410794
DOI: 10.1371/journal.ppat.1011480 -
Journal of Virology Oct 2023Pathogens often hijack extracellular vesicle (EV) biogenesis pathways for assembly, egress, and cell-to-cell spread. Herpes simplex virus 1 (HSV-1) infection stimulated...
Pathogens often hijack extracellular vesicle (EV) biogenesis pathways for assembly, egress, and cell-to-cell spread. Herpes simplex virus 1 (HSV-1) infection stimulated EV biogenesis through a CD63 tetraspanin biogenesis pathway and these EVs activated antiviral responses in recipient cells restricting the infection. HSV-1 inhibits autophagy to evade the host, and increased CD63 exocytosis could be a coping mechanism, as CD63 is involved in both cargo delivery to lysosomes during autophagy and exocytosis. We analyzed exocytosis after infection with two HSV-1 mutants, a ΔICP34.5 and a ΔICP0, that could not inhibit autophagy. Unlike HSV-1(F), neither of these viruses stimulated increased EV biogenesis through the CD63 pathway. ΔICP34.5 stimulated production of microvesicles and apoptotic bodies that were CD63-negative, while ΔICP0 displayed an overall reduced production of EVs. These EVs activated innate immunity gene expression in recipient cells. Given the potential use of these mutants for therapeutic purposes, the immunomodulatory properties of EVs associated with them may be beneficial.
Topics: Humans; Autophagy; Exocytosis; Herpes Simplex; Herpesvirus 1, Human; Tetraspanins
PubMed: 37712703
DOI: 10.1128/jvi.00757-23 -
Nature Apr 2024Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after...
Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1). Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.
Topics: Animals; Female; Humans; Male; Mice; Age of Onset; Alleles; COVID-19; DNA Polymerase gamma; DNA, Mitochondrial; Encephalitis Viruses, Tick-Borne; Encephalitis, Tick-Borne; Founder Effect; Gene Knock-In Techniques; Herpes Simplex; Herpesvirus 1, Human; Immune Tolerance; Immunity, Innate; Interferon Type I; Mitochondrial Diseases; Mutation; RNA, Mitochondrial; SARS-CoV-2
PubMed: 38570685
DOI: 10.1038/s41586-024-07260-z -
Cellular Signalling Sep 2023Corneal neovascularization (CNV) is a symptom of herpes simplex keratitis (HSK), which can result in blindness. The corneal angiogenesis brought on by herpes simplex...
BACKGROUND
Corneal neovascularization (CNV) is a symptom of herpes simplex keratitis (HSK), which can result in blindness. The corneal angiogenesis brought on by herpes simplex virus type 1 (HSV-1) is strongly affected by vascular endothelial growth factor A (VEGFA). The N-methyladenosine (mA) modification catalyzed by methyltransferase-like 3 (METTL3) is a crucial epigenetic regulatory process for angiogenic properties. However, the roles of METTL3 and mA in HSK-induced CNV remain unknown. Here, we investigated these roles in vitro and in vivo.
METHODS
A PCR array in HSV-1-infected human umbilical vein endothelial cells (HUVECs) was used to screen for METTL3 among the epitranscriptomic genes. Tube formation and scratch assays were conducted to investigate cell migration capacity. The global mRNA mA abundance was evaluated using a dot blot assay. Gene expression was assessed by RT-qPCR, western blotting, and fluorescence immunostaining. In addition, bioinformatic analysis was conducted to identify the downstream molecules of METTL3 in HUVECs. METTL3 knockdown and STM2457 treatment clarified the specific underlying molecular mechanisms affecting HSV-1-induced angiogenesis in vitro. An acute HSK mouse model was established to examine the effects of METTL3 knockdown or inhibition using STM2457 on pathological angiogenic development in vivo.
RESULTS
METTL3 was highly upregulated in HSV-1-infected HUVECs and led to increased mA levels. METTL3 knockdown or inhibition by STM2457 further reduced mA levels and VEGFA expression and impaired migration and tube formation capacity in HUVECs after HSV-1 infection. Mechanistically, METTL3 regulated LRP6 expression through post-transcriptional mRNA modification in an mA-dependent manner, increasing its stability, upregulating VEGFA expression, and promoting angiogenesis in HSV-1-infected HUVECs. Furthermore, METTL3 knockdown or inhibition by STM2457 reduced CNV in vivo.
CONCLUSION
Our findings revealed that METTL3 promotes pathological angiogenesis through canonical Wnt and VEGF signaling in vitro and in vivo, providing potential pharmacological targets for preventing the progression of CNV in HSK.
Topics: Animals; Mice; Humans; Corneal Neovascularization; Herpesvirus 1, Human; Vascular Endothelial Growth Factor A; Wnt Signaling Pathway; Keratitis, Herpetic; Neovascularization, Pathologic; Human Umbilical Vein Endothelial Cells; RNA, Messenger; Methyltransferases
PubMed: 37356601
DOI: 10.1016/j.cellsig.2023.110784 -
CNS Neuroscience & Therapeutics Jun 2024Neurodegenerative diseases (NDs) constitute a group of disorders characterized by the progressive deterioration of nervous system functionality. Currently, the precise... (Review)
Review
Neurodegenerative diseases (NDs) constitute a group of disorders characterized by the progressive deterioration of nervous system functionality. Currently, the precise etiological factors responsible for NDs remain incompletely elucidated, although it is probable that a combination of aging, genetic predisposition, and environmental stressors participate in this process. Accumulating evidence indicates that viral infections, especially neurotropic viruses, can contribute to the onset and progression of NDs. In this review, emerging evidence supporting the association between viral infection and NDs is summarized, and how the autophagy pathway mediated by viral infection can cause pathological aggregation of cellular proteins associated with various NDs is discussed. Furthermore, autophagy-related genes (ARGs) involved in Herpes simplex virus (HSV-1) infection and NDs are analyzed, and whether these genes could link HSV-1 infection to NDs is discussed. Elucidating the mechanisms underlying NDs is critical for developing targeted therapeutic approaches that prevent the onset and slow the progression of NDs.
Topics: Humans; Neurodegenerative Diseases; Autophagy; Animals; Virus Diseases; Herpesvirus 1, Human
PubMed: 38082503
DOI: 10.1111/cns.14548 -
Journal of Clinical Virology : the... Oct 2023Antiviral resistance in human herpes simplex viruses (HSV) remains a significant clinical challenge in immunocompromised populations. Although molecular tests have...
BACKGROUND
Antiviral resistance in human herpes simplex viruses (HSV) remains a significant clinical challenge in immunocompromised populations. Although molecular tests have largely replaced viral culture for HSV diagnosis and molecular antiviral resistance testing is available for many viruses, HSV resistance testing continues to rely on phenotypic, viral culture-based methods, requiring weeks for results. Consequently, treatment of suspected HSV resistance remains largely empiric.
METHODS
We used HSV whole genome sequencing and a database of previously characterized HSV acyclovir and foscarnet resistance mutations to evaluate the performance of genotypic antiviral resistance testing among 19 control strains compared to in-house plaque reduction assay (PRA) and 25 clinical isolates sent for reference lab PRA antiviral resistance testing.
RESULTS
Among control strains, 23/29 (79.3%) results were concordant, 5 (17.2%) were indeterminate, and 1 (3.4%) was discordant. Indeterminate results were caused by variants of uncertain significance (VUS), including mutations without published phenotypes and mutations with contradictory results. Among clinical isolates, 14/40 (35%) results were concordant, 17 (42.5%) were indeterminate, and 9 (22.5%) were discordant. All discordant results were in reportedly phenotypically-susceptible HSV-1 strains yet possessed resistance mutations. Three contained resistant subpopulations. 6/8 (75%) discordant phenotypes were concordant with resistant genotypes upon repeat PRA.
CONCLUSIONS
These data support the combination of genotypic and phenotypic testing to diagnose HSV resistance more accurately and likely more rapidly than phenotypic testing alone. Genotypic context of resistance mutations and the ability of viral strains to form plaques in culture may affect phenotypic resistance results, highlighting the limitations of PRA alone as a gold standard method.
Topics: Humans; Antiviral Agents; Herpesvirus 2, Human; Acyclovir; Foscarnet; Herpesvirus 1, Human; Genotype; Drug Resistance, Viral; Herpes Simplex
PubMed: 37586184
DOI: 10.1016/j.jcv.2023.105554 -
The Journal of Infectious Diseases Nov 2023Our study aimed to determine the risk of herpes zoster reactivation and coronavirus disease 2019 (COVID-19) vaccination (mRNA vaccine [BNT162b2] and adenovirus-vectored...
BACKGROUND
Our study aimed to determine the risk of herpes zoster reactivation and coronavirus disease 2019 (COVID-19) vaccination (mRNA vaccine [BNT162b2] and adenovirus-vectored vaccine [ChAdOx1 nCoV-19]).
METHODS
This retrospective study analyzed herpes zoster cases diagnosed between 26 February 2021 and 30 June 2021 and registered in the National Health Insurance Service database. A matched case-control study with a 1:3 matching ratio and a propensity score matching (PSM) study with a 1:1 ratio of vaccinated and unvaccinated individuals were performed.
RESULTS
In the matched case control analysis, BNT162b2 was associated with an increased risk of herpes zoster reactivation (first dose adjusted odds ratio [aOR], 1.11; 95% confidence interval [CI], 1.06-1.15; second dose aOR, 1.17; 95% CI, 1.12-1.23). PSM analysis revealed a statistically significant increase in risk within 18 days following any vaccination (adjusted hazard ratio [aHR], 1.09; 95% CI, 1.02-1.16). BNT162b2 was associated with an increased risk at 18 days postvaccination (aHR, 1.65; 95% CI, 1.35-2.02) and second dose (aHR, 1.10; 95% CI, 1.02-1.19). However, the risk did not increase in both analyses of ChAdOx1 vaccination.
CONCLUSIONS
mRNA COVID-19 vaccination possibly increases the risk of herpes zoster reactivation, and thus close follow-up for herpes zoster reactivation is required.
Topics: Humans; Adenoviridae; Adenoviridae Infections; BNT162 Vaccine; Case-Control Studies; ChAdOx1 nCoV-19; COVID-19; COVID-19 Vaccines; Herpes Zoster; Herpes Zoster Vaccine; Herpesvirus 3, Human; Retrospective Studies; Vaccination; Vaccines, Attenuated
PubMed: 37549237
DOI: 10.1093/infdis/jiad297 -
The Journal of Infectious Diseases Nov 2023Protection against herpes zoster is primarily conferred by cell-mediated immunity. However, anti-varicella-zoster virus (VZV) glycoprotein (anti-gp) antibody responses... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Protection against herpes zoster is primarily conferred by cell-mediated immunity. However, anti-varicella-zoster virus (VZV) glycoprotein (anti-gp) antibody responses to zoster vaccine live (ZVL) are correlated with protection, suggesting a potential protective role for antibody. Detailed studies of antibody responses to the recombinant zoster vaccine (RZV) are provided.
METHODS
We compared enzyme-linked immunosorbent assay-measured anti-VZV glycoproteins (anti-gp) and glycoprotein E (anti-gE) antibody levels and avidity in 159 participants randomized to RZV (n = 80) or ZVL (n = 79) recipients over 5 years after vaccination and identified predictors of antibody persistence.
RESULTS
The comparison between vaccine groups showed higher anti-gE and anti-gp antibody levels after RZV than after ZVL over the 5-year study duration. RZV recipients also had higher anti-gE avidity for 5 years and higher anti-gp avidity in the first year after vaccination. Compared with prevaccination levels, RZV recipients maintained higher levels of anti-gE antibodies and avidity for 5 years, whereas ZVL recipients only maintained higher anti-gE avidity. Anti-gp antibody levels and avidity decreased to prevaccination levels or below beyond 1 year after vaccination in both groups. Independent predictors of persistence of antibody levels and avidity included vaccine type, prevaccination and peak antibody levels and avidity, prevaccination and peak cell-mediated immunity, and age. Sex or prior ZVL administration did not affect persistence.
CONCLUSIONS
Antibody responses and avidity were higher and more persistent in RZV than in ZVL recipients. The effect of age on antibody persistence in RZV recipients is novel.
Topics: Humans; Herpes Zoster Vaccine; Antibody Formation; Herpes Zoster; Herpesvirus 3, Human; Glycoproteins; Vaccines, Synthetic
PubMed: 37141390
DOI: 10.1093/infdis/jiad132 -
The Interplay of Genital Herpes with Cellular Processes: A Pathogenesis and Therapeutic Perspective.Viruses Oct 2023Genital herpes, primarily caused by herpes simplex virus-2 (HSV-2), remains a pressing global health concern. Its remarkable ability to intertwine with cellular... (Review)
Review
Genital herpes, primarily caused by herpes simplex virus-2 (HSV-2), remains a pressing global health concern. Its remarkable ability to intertwine with cellular processes, from harnessing host machinery for replication to subverting antiviral defenses like autophagy and programmed cell death, exemplifies the intricate interplay at the heart of its pathogenesis. While the biomedical community has extensively researched antiviral interventions, the efficiency of these strategies in managing HSV-2 remains suboptimal. Recognizing this, attention has shifted toward leveraging host cellular components to regulate HSV-2 replication and influence the cell cycle. Furthermore, innovative interventional strategies-including drug repurposing, microbivacs, connecting the host microbiome, and exploiting natural secondary metabolites-are emerging as potential game changers. This review summarizes the key steps in HSV-2 pathogenesis and newly discovered cellular interactions, presenting the latest developments in the field, highlighting existing challenges, and offering a fresh perspective on HSV-2's pathogenesis and the potential avenues for its treatment by targeting cellular proteins and pathways.
Topics: Humans; Herpes Genitalis; Herpesvirus 2, Human; Autophagy; Antiviral Agents; Herpes Simplex
PubMed: 38005873
DOI: 10.3390/v15112195