A5062742278- interferon and immune responses
- SARS-CoV-2 and COVID-19 Research
- COVID-19 Clinical Research Studies
- Autophagy in Disease and Therapy
- Immune Response and Inflammation
- Inflammasome and immune disorders
- Long-Term Effects of COVID-19
- Phagocytosis and Immune Regulation
- RNA regulation and disease
- Viral Infections and Immunology Research
- Viral gastroenteritis research and epidemiology
- Viral Infections and Outbreaks Research
- Antimicrobial Peptides and Activities
- Virus-based gene therapy research
- Research on Leishmaniasis Studies
- Viral Infections and Vectors
- Extracellular vesicles in disease
- CRISPR and Genetic Engineering
- Infectious Encephalopathies and Encephalitis
- Lipid Membrane Structure and Behavior
- Bacillus and Francisella bacterial research
- Retinoids in leukemia and cellular processes
- RNA and protein synthesis mechanisms
Universität Ulm
2020-2025
University Medical Center
2025
A viral block on host protein synthesis As the coronavirus disease 2019 (COVID-19) pandemic continues to cause devastation, scientists race increase their understanding of disease-causing severe acute respiratory syndrome 2. Once inside cells, not only does virus hijack cells' translational machinery make proteins, but virulence factor nonstructural 1 (Nsp1) also shuts down translation messenger RNA. Thoms et al. determined a 2.6-angstrom resolution cryo–electron microscopy structure...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades most innate immune responses but may still be vulnerable to some. Here, we systematically analyze the impact of SARS-CoV-2 proteins on interferon (IFN) and autophagy. We show that synergize counteract anti-viral responses. For example, Nsp14 targets type I IFN receptor for lysosomal degradation, ORF3a prevents fusion autophagosomes lysosomes, ORF7a interferes with autophagosome acidification. Most activities are...
SARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of tract against limited, we generated screened peptide/protein library derived from bronchoalveolar lavage for inhibitors spike-driven entry. Analysis antiviral fractions revealed presence α1-antitrypsin (α1AT), highly abundant circulating serine protease inhibitor. Here, report that α1AT inhibits entry at physiological concentrations suppresses viral replication in...
Abstract Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination achieved through autophagic degradation or recycling STING retrograde Golgi-to-ER transport. Here, we identify GTPase ADP-ribosylation factor 1 (ARF1) as a crucial negative regulator cGAS-STING Heterozygous ARF1 missense mutations cause...
The IFN system constitutes a powerful antiviral defense machinery. Consequently, effective responses protect against severe COVID-19 and exogenous IFNs inhibit SARS-CoV-2 in vitro. However, emerging variants of concern (VOCs) may have evolved reduced sensitivity. Here, we determined differences replication susceptibility an early isolate (NL-02-2020) the Alpha, Beta, Gamma, Delta, Omicron VOCs Calu-3 cells, iPSC-derived alveolar type-II cells (iAT2) air–liquid interface (ALI) cultures...
Type I interferons (IFN-I) are critical mediators of innate control viral infections but also drive the recruitment inflammatory cells to sites infection, a key feature severe coronavirus disease 2019. Here, IFN-I signaling was modulated in rhesus macaques (RMs) before and during acute SARS-CoV-2 (severe respiratory syndrome 2) infection using mutated IFN-α2 (IFN-modulator; IFNmod), which has previously been shown reduce binding endogenous IFN-I. IFNmod treatment uninfected RMs observed...
Sensing of human immunodeficiency virus type 1 (HIV-1) DNA is mediated by the cyclic GMP-AMP synthase-stimulator interferon genes (cGAS-STING) signaling axis. Signal transduction and regulation this cascade achieved post-translational modifications. Here we show that cGAS-STING-dependent HIV-1 sensing requires interferon-stimulated gene 15 (ISG15). ISG15 deficiency inhibits STING-dependent STING agonist-induced antiviral response. Upon external stimuli, undergoes ISGylation at residues K224,...
Abstract SARS-CoV-2 is the causative agent of current COVID-19 pandemic. A major virulence factor SARS-CoVs nonstructural protein 1 (Nsp1) which suppresses host gene expression by ribosome association via an unknown mechanism. Here, we show that Nsp1 from binds to 40S and 80S ribosomes, resulting in shutdown capped mRNA translation both vitro cells. Structural analysis cryo-electron microscopy (cryo-EM) reconstituted Nsp1-40S native human Nsp1-ribosome complexes revealed C-terminus obstructs...
Oligoadenylate synthetase (OAS) proteins are immune sensors for double-stranded RNA and critical restricting viruses. OAS2 comprises two OAS domains, only one of which can synthesize 2'-5'-oligoadenylates RNase L activation. Existing structures OAS1 provide a model enzyme activation, but do not explain how multiple domains discriminate length. Here, we discover that exists in an autoinhibited state as zinc-mediated dimer present mechanism length discrimination: the catalytically deficient...
Tight control of cGAS-STING-mediated DNA sensing is crucial to avoid auto-inflammation. The GTPase ADP-ribosylation factor 1 (ARF1) maintain cGAS-STING homeostasis and various pathogenic ARF1 variants are associated with type I interferonopathies. Functional inhibits STING activity by maintaining mitochondrial integrity facilitating COPI-mediated retrograde trafficking deactivation. Yet the factors governing two distinct functions remained unexplored. Here, we dissect ARF1's dual role a...
<title>Abstract</title> Sensing of viral pathogens by RIG-I-like receptors (RLRs) requires their priming via dephosphorylation mediated the protein phosphatase 1 regulatory subunit 12C (R12C), which is activated upon virus-induced actin rearrangements. Here, we show that HIV-1 accessory Nef disrupts R12C-mediated RLR priming, thereby preventing efficient sensing. variants containing single point mutations in (F/R191A) ablate its ability to bind actin-modulating kinase PAK2 trigger increased...
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes disease 2019 (COVID-19). To identify factors of the tract that suppress SARS-CoV-2, we screened a peptide/protein library derived from bronchoalveolar lavage, and identified α1-antitrypsin (α1-AT) as specific inhibitor SARS-CoV-2. α1-AT targets viral spike protein blocks SARS-CoV-2 infection human airway epithelium at physiological concentrations. Our findings show endogenous restricts repurposes α1-AT-based drugs...
Infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causative agent of COVID-19 pandemic, leads to profound remodeling cellular membranes, promoting viral replication and virion assembly. A full understanding this drastic process morphogenesis remains lacking. In study, we applied room temperature transmission electron microscopy (TEM) scanning (STEM) tomography visualize SARS-CoV-2 factory in Vero cells, present our results comparison published cryo-EM studies....
Abstract Type-I interferons (IFN-I) are critical mediators of innate control viral infections, but also drive recruitment inflammatory cells to sites infection, a key feature severe COVID-19. Here, and for the first time, IFN-I signaling was modulated in rhesus macaques (RMs) prior during acute SARS-CoV-2 infection using mutated IFNα2 (IFN-modulator; IFNmod), which has previously been shown reduce binding endogenous IFN-I. In SARS-CoV-2-infected RMs, IFNmod reduced both antiviral ISGs....
We present a protocol for analyzing the impact of SARS-CoV-2 proteins in interferon signaling using luciferase reporter assays. Here, induction defined promoters can be quantitatively assessed with high sensitivity and broad linear range. The results are similar to those obtained qPCR measure endogenous mRNA induction. assay requires stringent normalization confirmation more physiological settings. is adaptable other viruses innate immune stimuli. For complete details on use execution this...
ABSTRACT The innate immune system constitutes a powerful barrier against viral infections. However, it may fail because successful emerging pathogens, like SARS-CoV-2, evolved strategies to counteract it. Here, we systematically assessed the impact of 29 SARS-CoV-2 proteins on sensing, type I, II and III interferon (IFN) signaling, autophagy inflammasome formation. Mechanistic analyses show that I IFN responses are effectively counteracted at different levels. For example, Nsp14 induces loss...
Translating the CRISPR/Cas9 genome editing technology into clinics is still hampered by rather unspecific, unsafe and/or inconvenient approaches for delivery of its main components - Cas9 endonuclease and a guide RNA cells. Here, we describe development novel transient non-viral strategy based on translocation machinery Bacillus anthracis anthrax toxin, PA (protective antigen). We show that variants fused to N-terminus lethal factor or hexahistidine tag are shuttled through channels formed...
ABSTRACT To date, five variants of concern (VOCs) SARS-CoV-2 have emerged that show increased fitness and/or immune evasion. While the continuously evolving escape from humoral responses has been analyzed in detail, adaptation to human innate defenses such as autophagy is less understood. Here, we demonstrate mutation T9I structural envelope (E) protein confers resistance Omicron VOCs (BA.1, BA.5 and XBB.1.5) compared 2020 or Delta VOC. Mechanistic analyses revealed Omicron-associated E...
ABSTRACT Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP AMP synthase (cGAS), stimulator genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination achieved through autophagic degradation or recycling STING retrograde Golgi-to-ER transport. Here, we identify GTPase ARF1 as a crucial negative regulator cGAS-STING signaling. Heterozygous missense mutations cause novel type interferonopathy...