Anti-SARS-CoV-2 Small Molecule Targeting of Oxysterol-Binding Protein (OSBP) Activates Cellular Antiviral Innate Immunity DOI Creative Commons
Subramaniyan Bharathiraja,

Emily C. Falcon,

A. Moore

et al.

ACS Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: April 21, 2025

Human oxysterol-binding protein (OSBP) is a potentially druggable mediator in the replication of broad spectrum positive-sense (+) single-stranded RNA (ssRNA) viruses, including members Picornaviridae, Flaviviridae, and Coronaviridae. OSBP cytoplasmic lipid transporting capable moving cholesterol phosphoinositides between endoplasmic reticulum (ER) Golgi, ER lysosome. Several structurally diverse antiviral compounds have been reported to function through targeting OSBP, natural product compound OSW-1. Our prior work shows that transient OSW-1 treatment induces reduction levels over multiple successive cell generations (i.e., multigenerational), with no apparent cellular toxicity, OSW-1-induced has activity against (+)ssRNA viruses. This study extends these findings establishes vitro pathogenic human rhinovirus (HRV1B), feline coronavirus peritonitis virus (FIPV), 229E (HCoV-229E), severe acute respiratory syndrome 2 (SARS-CoV-2). We also demonstrate airway epithelial cells alters expression innate immune mediators, interferon (IFN) related genes IFNB1, IFNL3, CXCL10, ISG15, MX1. Furthermore, enhances induction specific components type I III IFN responses triggered by viral mimetic polyinosinic-polycytidylic acid (Poly IC). In summary, this further demonstrates importance presents as potential regulator responses.

Language: Английский

Viral recognition and the antiviral interferon response DOI Creative Commons
Louise Dalskov, Hans Henrik Gad, Rune Hartmann

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(14)

Published: June 27, 2023

Language: Английский

Citations

55
Protein Quality Control Systems and ER Stress as Key Players in SARS-CoV-2-Induced Neurodegeneration DOI Creative Commons
Elena Gavilán, Rafael Medina-Guzman, Bazhena Bahatyrevich-Kharitonik

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(2), P. 123 - 123

Published: Jan. 9, 2024

The COVID-19 pandemic has brought to the forefront intricate relationship between SARS-CoV-2 and its impact on neurological complications, including potential links neurodegenerative processes, characterized by a dysfunction of protein quality control systems ER stress. This review article explores role systems, such as Unfolded Protein Response (UPR), Endoplasmic Reticulum-Associated Degradation (ERAD), Ubiquitin–Proteasome System (UPS), autophagy molecular chaperones, in infection. Our hypothesis suggests that produces stress exploits leading disruption proteostasis cannot be solved host cell. culminates cell death may represent link neurodegeneration.

Language: Английский

Citations

14
Interference without interferon: interferon-independent induction of interferon-stimulated genes and its role in cellular innate immunity DOI Creative Commons
Shachee Swaraj, Shashank Tripathi

mBio, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 20, 2024

ABSTRACT Interferons (IFNs) are multifaceted proteins that play pivotal roles in orchestrating robust antiviral immune responses and modulating the intricate landscape of host immunity. The major signaling pathway activated by IFNs is JAK/STAT (Janus kinase/signal transducer activator transcription) pathway, which leads to transcription a battery genes, collectively known as IFN-stimulated genes (ISGs). While well-established role coordinating innate response against viral infections widely acknowledged, recent years have provided more distinct comprehension functional significance attributed non-canonical, IFN-independent induction ISGs. In this review, we summarize non-conventional pathways ISG induction. These alternative offer new avenues for developing strategies or immunomodulation various diseases.

Language: Английский

Citations

8
Investigating the Evolution of Drosophila STING-Dependent Antiviral Innate Immunity by Multispecies Comparison of 2′3′-cGAMP Responses DOI Creative Commons

Léna Hédelin,

Antonin Thiébaut, Jingxian Huang

et al.

Molecular Biology and Evolution, Journal Year: 2024, Volume and Issue: 41(3)

Published: Feb. 20, 2024

Viruses represent a major threat to all animals, which defend themselves through induction of large set virus-stimulated genes that collectively control the infection. In vertebrates, these include interferons play critical role in amplification response Virus- and interferon-stimulated restriction factors targeting different steps viral replication cycle, addition molecules associated with inflammation adaptive immunity. Predictably, antiviral evolve dynamically pressure. As result, each animal has unique arsenal genes. Here, we exploit capacity experimentally activate evolutionarily conserved stimulator IFN (STING) signaling pathway by injection cyclic dinucleotide 2'3'-cyclic guanosine monophosphate-adenosine monophosphate into flies define repertoire STING-regulated 10 Drosophila species, spanning 40 million years evolution. Our data reveal factors, including STING itself, cGAS-like-receptor, factor pastel, protein Vago, but also 2 key components RNA interference pathway, Dicer-2, Argonaute2. addition, identify unknown species- or lineage-specific have not been previously resistance viruses. provide insight core pave way for characterization effectors.

Language: Английский

Citations

7
Serpine1 mRNA confers mesenchymal characteristics to the cell and promotes CD8+ T cells exclusion from colon adenocarcinomas DOI Creative Commons
Salvador Polo-Generelo, Cristina Rodríguez-Mateo, Belén Torres

et al.

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: March 6, 2024

Abstract Serine protease inhibitor clade E member 1 (SERPINE1) inhibits extracellular matrix proteolysis and cell detachment. However, SERPINE1 expression also promotes tumor progression plays a crucial role in metastasis. Here, we solve this apparent paradox report that Serpine1 mRNA per se, independent of its protein-coding function, confers mesenchymal properties to the cell, promoting migration, invasiveness, resistance anoikis increasing glycolytic activity by sequestering miRNAs. Expression upregulates TRA2B splicing factor without affecting levels. Through transcriptional profiling, found downregulates through genes involved immune response. Analysis human colon samples showed an inverse correlation between CD8+ T infiltration, unveiling potential value as promising therapeutic target for tumors.

Language: Английский

Citations

7
Proinflammatory Cytokines in Chronic Respiratory Diseases and Their Management DOI Creative Commons
Vivek P. Chavda, Rajashri Bezbaruah, Nasima Ahmed

et al.

Cells, Journal Year: 2025, Volume and Issue: 14(6), P. 400 - 400

Published: March 9, 2025

Pulmonary homeostasis can be agitated either by external environmental insults or endogenous factors produced during respiratory/pulmonary diseases. The lungs counter these initiating mechanisms of inflammation as a localized, non-specific first-line defense response. Cytokines are small signaling glycoprotein molecules that control the immune They formed numerous categories cell types and induce movement, growth, differentiation, death cells. During respiratory diseases, multiple proinflammatory cytokines play crucial role in orchestrating chronic structural changes tract recruiting inflammatory cells maintaining release growth to maintain inflammation. issue aggravates when response is exaggerated and/or cytokine production becomes dysregulated. In such instances, unresolving reactions accelerate airway remodeling maladaptive outcomes. Pro-inflammatory generate deleterious consequences through interactions with receptors, which turn initiate signal cell, triggering profile cascade seen different pulmonary diseases vary have become fundamental targets for advancement new therapeutic strategies lung There considerable approaches target cytokine-mediated diseases; however, blocking specific may not contribute clinical benefit. Alternatively, broad-spectrum anti-inflammatory more likely clinically effective. Herein, this comprehensive review literature identifies various (e.g., interleukins, chemokines, factors) involved pathogenesis asthma, obstructive pulmonary, cancer, pneumonia, fibrosis) investigates targeted treatment approaches.

Language: Английский

Citations

1
Comparative Efficacy and Safety of Three Janus Kinase Inhibitors in Ulcerative Colitis: A Real‐World Multicentre Study in Japan DOI
Shintaro Akiyama, Hiromichi Shimizu,

Akiko Tamura

et al.

Alimentary Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

ABSTRACT Background Three Janus kinase (JAK) inhibitors are approved for ulcerative colitis (UC) in Japan. Aim To compare the real‐world efficacy and safety of these three JAK UC. Methods This was a multicentre, retrospective study patients with UC started on inhibitors. The primary outcome clinical remission at 10, 26 58 weeks, most recent follow‐up. among inhibitors, we created matched cohorts (upadacitinib vs. filgotinib, tofacitinib filgotinib upadacitinib tofacitinib) using propensity score matching. Results We identified 228 upadacitinib‐treated (median follow‐up 49 weeks; IQR 25–72), 215 filgotinib‐treated (follow‐up 56 17–82) 159 tofacitinib‐treated 112 10–258). Clinical rates upadacitinib, were 72.8%, 50.6% 45.8%, respectively. Over 70% previously treated other biologics or achieved upadacitinib. On multivariate analysis, number previous advanced therapies inversely associated tofacitinib. Comparative analysis showed that had higher lower risk discontinuation than However, significant acne. Conclusions Considering particularly high even refractory UC, may be considered as an upfront inhibitor before

Language: Английский

Citations

6
Human Betacoronavirus OC43 Interferes with the Integrated Stress Response Pathway in Infected Cells DOI Creative Commons
Stacia M. Dolliver,

Caleb Galbraith,

Denys A. Khaperskyy

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(2), P. 212 - 212

Published: Jan. 31, 2024

Viruses evolve many strategies to ensure the efficient synthesis of their proteins. One such strategy is inhibition integrated stress response—the mechanism through which infected cells arrest translation phosphorylation alpha subunit eukaryotic initiation factor 2 (eIF2α). We have recently shown that human common cold betacoronavirus OC43 actively inhibits eIF2α in response sodium arsenite, a potent inducer oxidative stress. In this work, we examined modulation responses by and demonstrated negative feedback regulator GADD34 strongly induced cells. However, upregulation expression was independent from activation not required for virus-infected Our work reveals complex interplay between coronavirus response, viral protein ensured but loop disrupted.

Language: Английский

Citations

5
Role of type-I and type-III interferons in gastrointestinal homeostasis and pathogenesis DOI Creative Commons
Austin P Wright, Timothy J. Nice

Current Opinion in Immunology, Journal Year: 2024, Volume and Issue: 86, P. 102412 - 102412

Published: Feb. 1, 2024

Language: Английский

Citations

5
An evolutionary perspective to innate antiviral immunity in animals DOI Creative Commons
João T. Marques, Carine Meignin, Jean‐Luc Imler

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(9), P. 114678 - 114678

Published: Aug. 27, 2024

Viruses pose a significant threat to cellular organisms.Innate antiviral immunity encompasses both RNA-and protein-based mechanisms designed sense and respond infections, fundamental aspect present in all living organisms.A potent RNA-based mechanism is RNA interference, where small RNA-programmed nucleases target viral RNAs.Protein-based often rely on the induction of transcriptional responses triggered by recognition infections through innate immune receptors.These involve upregulation genes aimed at countering infections.In this review, we delve into recent advances understanding diversification animals.An evolutionary perspective gains losses diverse animals coupled mechanistic studies model organisms such as fruit fly Drosophila melanogaster essential provide deep that can be translated new strategies treatment diseases.

Language: Английский

Citations

5