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Microbiome Jan 2021Polintons are large mobile genetic elements found in the genomes of eukaryotic organisms that are considered the ancient ancestors of most eukaryotic dsDNA viruses....
BACKGROUND
Polintons are large mobile genetic elements found in the genomes of eukaryotic organisms that are considered the ancient ancestors of most eukaryotic dsDNA viruses. Originally considered as transposons, they have been found to encode virus capsid genes, suggesting they may actually be integrated viruses; however, an extracellular form has yet to be detected. Recently, circa 25 Polinton-like viruses have been discovered in environmental metagenomes and algal genomes, which shared distantly related genes to both Polintons and virophages (Lavidaviridae). These entities could be the first members of a major class of ancient eukaryotic viruses; however, owing to the lack of available genomes for analysis, information on their global diversity, evolutionary relationships, eukaryotic hosts, and status as free virus particles is limited.
RESULTS
Here, we analysed the metaviromes of an alpine lake to show that Polinton-like virus genome sequences are abundant in the water column. We identify major capsid protein genes belonging to 82 new Polinton-like viruses and use these to interrogate publicly available metagenomic datasets, identifying 543 genomes and a further 16 integrated into eukaryotic genomes. Using an analysis of shared gene content and major capsid protein phylogeny, we define large groups of Polinton-like viruses and link them to diverse eukaryotic hosts, including a new group of viruses, which possess all the core genes of virophages and infect oomycetes and Chrysophyceae.
CONCLUSIONS
Our study increased the number of known Polinton-like viruses by 25-fold, identifying five major new groups of eukaryotic viruses, which until now have been hidden in metagenomic datasets. The large enrichment (> 100-fold) of Polinton-like virus sequences in the virus-sized fraction of this alpine lake and the fact that their viral major capsid proteins are found in eukaryotic host transcriptomes support the hypothesis that Polintons in unicellular eukaryotes are viruses. In summary, our data reveals a diverse assemblage of globally distributed viruses, associated with a wide range of unicellular eukaryotic hosts. We anticipate that the methods we have developed for Polinton-like virus detection and the database of over 20,000 genes we present will allow for continued discovery and analysis of these new viral groups. Video abstract.
Topics: Aquatic Organisms; DNA Viruses; DNA, Viral; Ecosystem; Eukaryota; Genome, Viral; Lakes; Phylogeny; Virophages; Virus Integration
PubMed: 33436089
DOI: 10.1186/s40168-020-00956-0 -
Nucleic Acids Research Nov 2023The timing of transcription and replication must be carefully regulated for heavily-transcribed genomes of double-stranded DNA viruses: transcription of immediate...
The timing of transcription and replication must be carefully regulated for heavily-transcribed genomes of double-stranded DNA viruses: transcription of immediate early/early genes must decline as replication ramps up from the same genome-ensuring efficient and timely replication of viral genomes followed by their packaging by structural proteins. To understand how the prototypic DNA virus Epstein-Barr virus tackles the logistical challenge of switching from transcription to DNA replication, we examined the proteome at viral replication forks. Specifically, to transition from transcription, the viral DNA polymerase-processivity factor EA-D is SUMOylated by the epigenetic regulator and E3 SUMO-ligase KAP1/TRIM28. KAP1's SUMO2-ligase function is triggered by phosphorylation via the PI3K-related kinase ATM and the RNA polymerase II-associated helicase RECQ5 at the transcription machinery. SUMO2-EA-D then recruits the histone loader CAF1 and the methyltransferase SETDB1 to silence the parental genome via H3K9 methylation, prioritizing replication. Thus, a key viral protein and host DNA repair, epigenetic and transcription-replication interference pathways orchestrate the handover from transcription-to-replication, a fundamental feature of DNA viruses.
Topics: Humans; Ataxia Telangiectasia Mutated Proteins; DNA Helicases; DNA Replication; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Histones; Ubiquitin-Protein Ligases; Virus Replication
PubMed: 37852757
DOI: 10.1093/nar/gkad823 -
Microbiology Spectrum Jun 2023Anelloviruses represent the major and most diverse component of the healthy human virome, referred to as the anellome. In this study, we determined the anellome of 50...
Anelloviruses represent the major and most diverse component of the healthy human virome, referred to as the anellome. In this study, we determined the anellome of 50 blood donors, forming two sex- and age-matched groups. Anelloviruses were detected in 86% of the donors. The number of detected anelloviruses increased with age and was approximately twice as high in men as in women. A total of 349 complete or nearly complete genomes were classified as belonging to torque teno virus (TTV), torque teno mini virus (TTMV), and torque teno midi virus (TTMDV) anellovirus genera (197, 88, and 64 sequences, respectively). Most donors had intergenus (69.8%) or intragenus (72.1%) coinfections. Despite the limited number of sequences, intradonor recombination analysis showed 6 intragenus recombination events in ORF1. As thousands of anellovirus sequences have been described recently, we finally analyzed the global diversity of human anelloviruses. Species richness and diversity were close to saturation in each anellovirus genus. Recombination was found to be the main factor promoting diversity, although its effect was significantly lower in TTV than in TTMV and TTMDV. Overall, our results suggest that differences in diversity between genera may be caused by variations in the relative contribution of recombination. Anelloviruses are the most common human infectious viruses and are considered essentially harmless. Compared to other human viruses, they are characterized by enormous diversity, and recombination is suggested to play an important role in their diversification and evolution. Here, by analyzing the composition of the plasma anellome of 50 blood donors, we find that recombination is also a determinant of viral evolution at the intradonor level. On a larger scale, analysis of anellovirus sequences currently available in databases shows that their diversity is close to saturation and differs among the three human anellovirus genera and that recombination is the main factor explaining this intergenus variability. Global characterization of anellovirus diversity could provide clues about possible associations between certain virus variants and pathologies, as well as facilitate the implementation of unbiased PCR-based detection protocols, which may be relevant for using anelloviruses as endogenous markers of immune status.
Topics: Male; Humans; Female; Anelloviridae; DNA Virus Infections; Torque teno virus; Demography; Recombination, Genetic; DNA, Viral
PubMed: 37199659
DOI: 10.1128/spectrum.04928-22 -
Viruses Jan 2020DNA viruses that replicate in the nucleus encompass a range of ubiquitous and clinically important viruses, from acute pathogens to persistent tumor viruses. These... (Review)
Review
DNA viruses that replicate in the nucleus encompass a range of ubiquitous and clinically important viruses, from acute pathogens to persistent tumor viruses. These viruses must co-opt nuclear processes for the benefit of the virus, whilst evading host processes that would otherwise attenuate viral replication. Accordingly, DNA viruses induce the formation of membraneless assemblies termed viral replication compartments (VRCs). These compartments facilitate the spatial organization of viral processes and regulate virus-host interactions. Here, we review advances in our understanding of VRCs. We cover their initiation and formation, their function as the sites of viral processes, and aspects of their composition and organization. In doing so, we highlight ongoing and emerging areas of research highly pertinent to our understanding of nuclear-replicating DNA viruses.
Topics: Cell Nucleus; DNA Viruses; Host Microbial Interactions; Humans; Viral Proteins; Viral Replication Compartments; Virus Replication
PubMed: 32013091
DOI: 10.3390/v12020151 -
Cell Host & Microbe Apr 20226 years ago, I published a Cell Host and Microbe paper that described randomization of virus genetic populations during mosquito infection. From within the evolutionary...
6 years ago, I published a Cell Host and Microbe paper that described randomization of virus genetic populations during mosquito infection. From within the evolutionary chaos, however, there is an order that can reveal a virus' past. Using these insights, I forged a career harnessing virus evolution to understand epidemiological patterns.
Topics: Animals; DNA Viruses; Evolution, Molecular; Genetics, Population; Viruses
PubMed: 35421340
DOI: 10.1016/j.chom.2022.03.006 -
Signal Transduction and Targeted Therapy Feb 2021Sensing of pathogenic nucleic acids by pattern recognition receptors (PRR) not only initiates anti-microbe defense but causes inflammatory and autoimmune diseases. E3...
Sensing of pathogenic nucleic acids by pattern recognition receptors (PRR) not only initiates anti-microbe defense but causes inflammatory and autoimmune diseases. E3 ubiquitin ligase(s) critical in innate response need to be further identified. Here we report that the tripartite motif-containing E3 ubiquitin ligase TRIM41 is required to innate antiviral response through facilitating pathogenic nucleic acids-triggered signaling pathway. TRIM41 deficiency impairs the production of inflammatory cytokines and type I interferons in macrophages after transfection with nucleic acid-mimics and infection with both DNA and RNA viruses. In vivo, TRIM41 deficiency leads to impaired innate response against viruses. Mechanistically, TRIM41 directly interacts with BCL10 (B cell lymphoma 10), a core component of CARD proteins-BCL10 - MALT1 (CBM) complex, and modifies the Lys63-linked polyubiquitylation of BCL10, which, in turn, hubs NEMO for activation of NF-κB and TANK-binding kinase 1 (TBK1) - interferon regulatory factor 3 (IRF3) pathways. Our study suggests that TRIM41 is the potential universal E3 ubiquitin ligase responsible for Lys63 linkage of BCL10 during innate antiviral response, adding new insight into the molecular mechanism for the control of innate antiviral response.
Topics: B-Cell CLL-Lymphoma 10 Protein; DNA Viruses; Host-Pathogen Interactions; Humans; I-kappa B Kinase; Immunity, Innate; Interferon Regulatory Factor-3; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Nucleic Acids; Protein Serine-Threonine Kinases; RNA Viruses; Receptors, Pattern Recognition; Ubiquitin-Protein Ligases; Virus Diseases
PubMed: 33640899
DOI: 10.1038/s41392-021-00477-8 -
Viruses Oct 2021In recent years, a variety of circular replicase-encoding single-stranded (CRESS) DNA viruses and unclassified virus-like DNA elements have been discovered in a broad...
In recent years, a variety of circular replicase-encoding single-stranded (CRESS) DNA viruses and unclassified virus-like DNA elements have been discovered in a broad range of animal species and environmental samples. Key questions to be answered concern their presence in the human diet and their potential impact on disease emergence. Especially DNA elements termed bovine meat and milk factors (BMMF) are suspected to act as co-factors in the development of colon and breast cancer. To expand our knowledge on the occurrence of these potential pathogens in human nutrition, a total of 73 sheep and 40 goat milk samples were assayed by combining rolling circle amplification (RCA), PCR and Sanger sequencing. The present study further includes retail milk from the aforementioned species. We recovered 15 single stranded (ss) circular genomes. Of those, nine belong to the family and six are members of the unclassified group of BMMF. Thus, dairy sheep and goats add to dispersal of CRESS viruses and circular ssDNA elements, which enter the food chain via milk. The presence of these entities is therefore more widespread in than initially assumed and seems to be part of the common human nutrition.
Topics: Animals; Cattle; DNA Viruses; DNA, Circular; DNA, Single-Stranded; DNA, Viral; Genome, Viral; Germany; Goats; Milk; Phylogeny; Polymerase Chain Reaction; Sheep
PubMed: 34834982
DOI: 10.3390/v13112176 -
Current Issues in Molecular Biology 2020Modern genomic sequencing and bioinformatics approaches have detected numerous examples of DNA sequences derived from DNA and RNA virus genomes integrated into both... (Review)
Review
Modern genomic sequencing and bioinformatics approaches have detected numerous examples of DNA sequences derived from DNA and RNA virus genomes integrated into both vertebrate and insect genomes. Retroviruses encode RNA-dependent DNA polymerases (reverse transcriptases) and integrases that convert their RNA viral genomes into DNA proviruses and facilitate proviral DNA integration into the host genome. Surprisingly, DNA sequences derived from RNA viruses that do not encode these enzymes also occur in host genomes. Non-retroviral integrated RNA virus sequences (NIRVS) occur at relatively high frequency in the genomes of the arboviral vectors and , are not distributed randomly and possibly contribute to mosquito antiviral immunity, suggesting these mosquitoes could serve as a model system for unravelling the function of NIRVS. Here we address the following questions: What drives DNA synthesis from the genomes of non-retroviral RNA viruses? How does integration of virus cDNA into host DNA occur, and what is its biological function (if any)? We review current knowledge of viral integrations in insect genomes, hypothesize mechanisms of NIRVS formation and their potential impact on insect biology, particularly antiviral immunity, and suggest directions for future research.
Topics: Aedes; Animals; Computational Biology; DNA Viruses; Endogenous Retroviruses; Genome, Insect; Genomics; Host-Pathogen Interactions; Insecta; Mosquito Vectors; RNA Viruses; RNA, Small Interfering; Retroelements; Virus Integration
PubMed: 31167954
DOI: 10.21775/cimb.034.013 -
ACS Chemical Biology Aug 2023The constant and the sudden emergence of zoonotic human and animal viruses is a significant threat to human health, the world economy, and the world food supply. This...
The constant and the sudden emergence of zoonotic human and animal viruses is a significant threat to human health, the world economy, and the world food supply. This has necessitated the development of broad-spectrum therapeutic strategies to combat these emerging pathogens. Mechanisms that are essential for viral replication and propagation have been successfully targeted in the past to develop broad-spectrum therapeutics that can be readily repurposed to combat new zoonotic pathogens. Because of the importance of viral RNA capping enzymes to viral replication and pathogenesis, as well as their presence in both DNA and RNA viruses, these viral proteins have been a long-standing therapeutic target. Here, we use genome sequencing information and yeast-based platforms (YeRC0M) to identify, characterize, and target viral genome-encoded essential RNA capping enzymes from emerging strains of DNA viruses, i.e., Monkeypox virus and African Swine Fever Virus, which are a significant threat to human and domestic animal health. We first identified and biochemically characterized these viral RNA capping enzymes and their necessary protein domains. We observed significant differences in functional protein domains and organization for RNA capping enzymes from emerging DNA viruses in comparison to emerging RNA viruses. We also observed several differences in the biochemical properties of these viral RNA capping enzymes using our phenotypic yeast-based approaches (YeRC0M) as compared to the previous in vitro studies. Further, using directed evolution, we were able to identify inactivation and attenuation mutations in these essential viral RNA capping enzymes; these data could have implications on virus biocontainment as well as live attenuated vaccine development. We also developed methods that would facilitate high-throughput phenotypic screening to identify broad-spectrum inhibitors that selectively target viral RNA capping enzymes over host RNA capping enzymes. As demonstrated here, our approaches to identify, characterize, and target viral genome-encoded essential RNA capping enzymes are highly modular and can be readily adapted for targeting emerging viral pathogens as well as their variants that emerge in the future.
Topics: Animals; Humans; Swine; Saccharomyces cerevisiae; African Swine Fever Virus; Viruses; RNA, Viral; Virus Replication; DNA Viruses
PubMed: 37498174
DOI: 10.1021/acschembio.3c00243 -
FEMS Microbiology Reviews Jan 2024One continuous companion and one of the major players in the human blood virome are members of the Anelloviridae family. Anelloviruses are probably found in all humans,... (Review)
Review
One continuous companion and one of the major players in the human blood virome are members of the Anelloviridae family. Anelloviruses are probably found in all humans, infection occurs early in life and the composition (anellome) is thought to remain stable and personal during adulthood. The stable anellome implies a great balance between the host immune system and the virus. However, the lack of a robust culturing system hampers direct investigation of interactions between virus and host cells. Other techniques, however, including next generation sequencing, AnelloScan-antibody tests, evolution selection pressure analysis, and virus protein structures, do provide new insights into the interactions between anelloviruses and the host immune system. This review aims at providing an overview of the current knowledge on the immune mechanisms acting on anelloviruses and the countering viral mechanisms allowing immune evasion.
Topics: Humans; Adult; Anelloviridae; DNA Virus Infections; High-Throughput Nucleotide Sequencing; Immune Evasion
PubMed: 38337179
DOI: 10.1093/femsre/fuae005