Birth of protein folds and functions in the virome

Nature, Год журнала: 2024, Номер 633(8030), С. 710 - 717

Опубликована: Авг. 26, 2024

Abstract The rapid evolution of viruses generates proteins that are essential for infectivity and replication but with unknown functions, due to extreme sequence divergence 1 . Here, using a database 67,715 newly predicted protein structures from 4,463 eukaryotic viral species, we found 62% structurally distinct lack homologues in the AlphaFold 2,3 Among remaining 38% proteins, many have non-viral structural analogues revealed surprising similarities between human pathogens their hosts. Structural comparisons suggested putative functions up 25% unannotated including those roles evasion innate immunity. In particular, RNA ligase T-like phosphodiesterases were resemble phage-encoded hydrolyse host immune-activating cyclic dinucleotides 3′,3′- 2′,3′-cyclic GMP-AMP (cGAMP). Experimental analysis showed T encoded by avian poxviruses similarly cGAMP, showing T-mediated targeting cGAMP is an evolutionarily conserved mechanism immune present both bacteriophage viruses. Together, analyses presented here afford new opportunities identify mechanisms virus–host interactions common across virome.

Язык: Английский

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The monkeypox virus-host interplays

Cell Insight, Год журнала: 2024, Номер 3(5), С. 100185 - 100185

Опубликована: Июль 14, 2024

Monkeypox virus (MPXV) is a DNA belonging to the

Язык: Английский

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BFVD—a large repository of predicted viral protein structures

Nucleic Acids Research, Год журнала: 2024, Номер 53(D1), С. D340 - D347

Опубликована: Ноя. 22, 2024

Abstract The AlphaFold Protein Structure Database (AFDB) is the largest repository of accurately predicted structures with taxonomic labels. Despite providing predictions for over 214 million UniProt entries, AFDB does not cover viral sequences, severely limiting their study. To address this, we created Big Fantastic Virus (BFVD), a 351 242 protein by applying ColabFold to sequence representatives UniRef30 clusters. By utilizing homology searches across two petabases assembled sequencing data, improved 36% these structure beyond ColabFold’s initial results. BFVD holds unique repertoire as 62% its entries show no or low structural similarity existing repositories. We demonstrate how substantial fraction bacteriophage proteins, which remained unannotated based on can be matched similar from BFVD. In that, par AFDB, while holding nearly three orders magnitude fewer structures. an important virus-specific expansion repositories, offering new opportunities advance research. freely downloaded at bfvd.steineggerlab.workers.dev and queried using Foldseek labels bfvd.foldseek.com.

Язык: Английский

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Monkeypox virus infection of human astrocytes causes gasdermin B cleavage and pyroptosis

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(8)

Опубликована: Фев. 12, 2024

Monkeypox virus (MPXV) infections in humans cause neurological disorders while studies of MPXV-infected animals indicate that the penetrates brain. Pyroptosis is an inflammatory type regulated cell death, resulting from plasma membrane rupture (PMR) due to oligomerization cleaved gasdermins pore formation. Herein, we investigated human neural tropism MPXV compared another orthopoxvirus, vaccinia (VACV), as well its effects on immune responses and death. Astrocytes were most permissive (and VACV) infections, followed by microglia oligodendrocytes, with minimal infection neurons based plaque assays. Aberrant morphological changes evident astrocytes accompanied viral protein (I3) immunolabelling detection over 125 MPXV-encoded proteins lysates mass spectrometry. MPXV- VACV-infected showed increased expression gene transcripts ( IL12, IRF3, IL1B, TNFA, CASP1 , GSDMB ). However, specifically induced proteolytic cleavage gasdermin B (GSDMB) (50 kDa), appearance N-terminal-GSDMB (30 kDa) C-terminal- (18 fragments. was associated release lactate dehydrogenase cellular nucleic acid staining, indicative PMR. Pre-treatment dimethyl fumarate reduced PMR astrocytes. Human support productive infection, induction accompanying GSDMB-mediated pyroptosis. These findings clarify recently recognized neuropathogenic also offering potential therapeutic options.

Язык: Английский

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The immune modules conserved across the tree of life: Towards a definition of ancestral immunity

PLoS Biology, Год журнала: 2024, Номер 22(7), С. e3002717 - e3002717

Опубликована: Июль 15, 2024

Immune defence mechanisms exist across the tree of life in such diversity that prokaryotic antiviral responses have historically been considered unrelated to eukaryotic immunity. Mechanisms divergent eukaryotes were similarly believed be largely clade specific. However, recent data indicate a subset modules (domains and proteins) from prokaryote systems are conserved populate many stages innate immune pathways. In this Essay, we propose notion ancestral immunity, which corresponds set between prokaryotes eukaryotes. After offering typology speculate on selective pressures could led differential conservation specific domains life. The exploration immunity is its infancy appears full promises illuminate evolution, also identify decipher economic, ecological, therapeutic importance.

Язык: Английский

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Molecular mimicry as a mechanism of viral immune evasion and autoimmunity

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 30, 2024

Язык: Английский

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Innate Immune Response to MPOX Infection: Mechanisms and Immune Escape

Journal of Innate Immunity, Год журнала: 2024, Номер unknown

Опубликована: Авг. 13, 2024

The re-emergence of the Mpox (formerly monkeypox) in 2022 non-endemic countries has raised many concerns for global health due to its high transmissibility and mortality rate. A major challenge fighting is ability evade host's innate immune system, which first line defense against viral infections. encodes various proteins that interfere with key antiviral pathways mechanisms, such as nuclear factor kappa B (NF-κB) signaling, cytokine production, complement inflammasome activation, chemokine binding. These modulate expression function mediators, interferons, interleukins, toll-like receptors, impair recruitment activation cells, natural killer cells. By suppressing or altering these responses, enhances replication infection host tissues organs, leading systemic inflammation, tissue damage, organ failure. This study reveals new insights into molecular cellular interactions between host’s immunity identifies potential targets strategies interventions.

Язык: Английский

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BFVD - a large repository of predicted viral protein structures

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 9, 2024

The AlphaFold Protein Structure Database (AFDB) is the largest repository of accurately predicted structures with taxonomic labels. Despite providing predictions for over 214 million UniProt entries, AFDB does not cover viral sequences, severely limiting their study. To bridge this gap, we created Big Fantastic Virus (BFVD), a 351,242 protein by applying ColabFold to sequence representatives UniRef30 clusters. BFVD holds unique repertoire as 63% its entries show no or low structural similarity existing repositories. We demonstrate how substantially enhances fraction annotated bacteriophage proteins compared sequence-based annotation using Bakta. In that, on par AFDB, while holding nearly three orders magnitude fewer structures. an important virus-specific expansion structure repositories, offering new opportunities advance research. freely available at https://bfvd.steineggerlab.workers.dev/

Язык: Английский

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Hospital-acquired catheter-associated urinary tract infections in critical care unit dogs with high rates of multidrug-resistant organisms.

PubMed, Год журнала: 2025, Номер 15(1), С. 339 - 347

Опубликована: Янв. 1, 2025

Urethral catheterization in the critical care unit often compromises urinary tract's defense mechanisms of canine patients and potentially leads to hospital-acquired systemic infection. Clinical signs catheter-associated tract infections (CAUTIs) are frequently absent dogs. This study aimed evaluate correlation between urinalysis results CAUTIs dogs assess impact prior antibiotic treatment for underlying diseases antibiotic-resistant bacteria. Twenty-eight underwent urethral Kasetsart University Veterinary Teaching Hospital. Bacterial cultures drug sensitivity tests were performed immediately after catheter placement (day 0), 3, 7 before removal. A positive urine culture was defined as ≥104 CFU/ml. Urinalysis parameters included pH, specific gravity, proteinuria, bacteriuria, pyuria, hematuria. Only with culture-negative on day 0 included. Data analyzed using GraphPad Prism version 10.0.2. Kaplan-Meier survival analysis used probability being free from over time. No significant association observed parameters, duration, breed, sex, neutering status, or age. Dogs pretreated antibiotics exhibited CAUTI-free periods longer than previously reported. The showed that probabilities 92.8% at 3 days, declining 60.7% by days 53.6% 10 days. Alarmingly, 80% isolates (12/15) multidrug-resistant organisms (MDRO) resistant ≥3 antimicrobials. high incidence detected 13 28 cases (46.4%). stayed hospital without CAUTIs. routine is unreliable predicting rate MDRO among underscores urgent need judicious use enhanced diagnostic methods settings. proposes serial bacterial combined modified sediment examinations can better manage CAUTI detection reduce growth MDROs veterinary practice.

Язык: Английский

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Temporal expression classes and functions of vaccinia virus and mpox (monkeypox) virus genes

mBio, Год журнала: 2025, Номер unknown

Опубликована: Март 20, 2025

ABSTRACT Poxviruses comprise pathogens that are highly pathogenic to humans and animals, causing diseases such as smallpox mpox (formerly monkeypox). The family also contains members developed vaccine vectors oncolytic agents fight other diseases. Vaccinia virus is the prototype poxvirus used eradicate smallpox. Poxvirus genes follow a cascade temporal expression pattern, categorized into early, intermediate, late stages using distinct transcription factors. This review comprehensively summarized classification of over 200 vaccinia genes. relationships between classes functions, well different branches immune responses, were discussed. Based on orthologs, we classified all genes, including few not previously annotated with orthologs in viruses. Additionally, reviewed functions based up-to-date published papers. provides readily usable resource for researchers working biology, medical countermeasures, utility development.

Язык: Английский

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