The arms race between bacteria and phages led to the development of sophisticated antiphage defense systems, including CRISPR-Cas and restriction-modification systems. Evidence suggests that known ...and unknown defense systems are located in "defense islands" in microbial genomes. Here, we comprehensively characterized the bacterial defensive arsenal by examining gene families that are clustered next to known defense genes in prokaryotic genomes. Candidate defense systems were systematically engineered and validated in model bacteria for their antiphage activities. We report nine previously unknown antiphage systems and one antiplasmid system that are widespread in microbes and strongly protect against foreign invaders. These include systems that adopted components of the bacterial flagella and condensin complexes. Our data also suggest a common, ancient ancestry of innate immunity components shared between animals, plants, and bacteria.
The evolutionary pressure imposed by phage predation on bacteria and archaea has resulted in the development of effective anti-phage defence mechanisms, including restriction-modification and ...CRISPR-Cas systems. Here, we report on a new defence system, DISARM (defence island system associated with restriction-modification), which is widespread in bacteria and archaea. DISARM is composed of five genes, including a DNA methylase and four other genes annotated as a helicase domain, a phospholipase D (PLD) domain, a DUF1998 domain and a gene of unknown function. Engineering the Bacillus paralicheniformis 9945a DISARM system into Bacillus subtilis has rendered the engineered bacteria protected against phages from all three major families of tailed double-stranded DNA phages. Using a series of gene deletions, we show that four of the five genes are essential for DISARM-mediated defence, with the fifth (PLD) being redundant for defence against some of the phages. We further show that DISARM restricts incoming phage DNA and that the B. paralicheniformis DISARM methylase modifies host CCWGG motifs as a marker of self DNA akin to restriction-modification systems. Our results suggest that DISARM is a new type of multi-gene restriction-modification module, expanding the arsenal of defence systems known to be at the disposal of prokaryotes against their viruses.
Bacteriophages, discovered about a century ago, have been pivotal as models for understanding the fundamental principles of molecular biology. While interest in phage biology declined after the phage ...“golden era,” key recent developments, including advances in phage genomics, microscopy, and the discovery of the CRISPR-Cas anti-phage defense system, have sparked a renaissance in phage research in the past decade. This review highlights recently discovered unexpected complexities in phage biology, describes a new arsenal of phage genes that help them overcome bacterial defenses, and discusses advances toward documentation of the phage biodiversity on a global scale.
Bacteriophages, which served as key model systems in the early days of molecular biology, are at the center of surprising recent discoveries regarding their mechanisms of infection, diversity, and development of genome engineering tools.
Sterile alpha and TIR motif-containing 1 (SARM1) is a protein involved in programmed death of injured axons. Following axon injury or a drug-induced insult, the TIR domain of SARM1 degrades the ...essential molecule nicotinamide adenine dinucleotide (NAD+), leading to a form of axonal death called Wallerian degeneration. Degradation of NAD+ by SARM1 is essential for the Wallerian degeneration process, but accumulating evidence suggest that other activities of SARM1, beyond the mere degradation of NAD+, may be necessary for programmed axonal death. In this study we show that the TIR domains of both human and fruit fly SARM1 produce 1''-2' and 1''-3' glycocyclic ADP-ribose (gcADPR) molecules as minor products. As previously reported, we observed that SARM1 TIR domains mostly convert NAD+ to ADPR (for human SARM1) or cADPR (in the case of SARM1 from Drosophila melanogaster). However, we now show that human and Drosophila SARM1 additionally convert ~0.1-0.5% of NAD+ into gcADPR molecules. We find that SARM1 TIR domains produce gcADPR molecules both when purified in vitro and when expressed in bacterial cells. Given that gcADPR is a second messenger involved in programmed cell death in bacteria and likely in plants, we propose that gcADPR may play a role in SARM1-induced programmed axonal death in animals.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Individualized survival prognostic models for symptomatic patients with appendicular metastatic bone disease are key to guiding clinical decision-making for the orthopedic surgeon. Several prognostic ...models have been developed in recent years; however, most orthopedic surgeons have not incorporated these models into routine practice. This is possibly due to uncertainty concerning their accuracy and the lack of comparison publications and recommendations. Our aim was to conduct a review and quality assessment of these models. A computerized literature search in MEDLINE, EMBASE and PubMed up to February 2022 was done, using keywords: “Bone metastasis”, “survival”, “extremity” and “prognosis”. We evaluated each model’s performance, assessing the estimated discriminative power and calibration accuracy for the analyzed patients. We included 11 studies out of the 1779 citations initially retrieved. The 11 studies included seven different models for estimating survival. Among externally validated survival prediction scores, PATHFx 3.0, 2013-SPRING and potentially Optimodel were found to be the best models in terms of performance. Currently, it is still a challenge to recommend any of the models as the standard for predicting survival for these patients. However, some models show better performance status and other quality characteristics. We recommend future, large, multicenter, prospective studies to compare between PATHfx 3.0, SPRING 2013 and OptiModel using the same external validation dataset.
Extracellular membrane vesicles from bacteria are now shown to transfer phage receptors from susceptible to resistant cells, thus making them transiently sensitive to phage infection (Tzipilevich ...et al.).
Extracellular membrane vesicles from bacteria are now shown to transfer phage receptors from susceptible to resistant cells, thus making them transiently sensitive to phage infection (Tzipilevich et al.).
The perpetual arms race between bacteria and phage has resulted in the evolution of efficient resistance systems that protect bacteria from phage infection. Such systems, which include the CRISPR‐Cas ...and restriction‐modification systems, have proven to be invaluable in the biotechnology and dairy industries. Here, we report on a six‐gene cassette in Bacillus cereus which, when integrated into the Bacillus subtilis genome, confers resistance to a broad range of phages, including both virulent and temperate ones. This cassette includes a putative Lon‐like protease, an alkaline phosphatase domain protein, a putative RNA‐binding protein, a DNA methylase, an ATPase‐domain protein, and a protein of unknown function. We denote this novel defense system BREX (Bacteriophage Exclusion) and show that it allows phage adsorption but blocks phage DNA replication. Furthermore, our results suggest that methylation on non‐palindromic TAGGAG motifs in the bacterial genome guides self/non‐self discrimination and is essential for the defensive function of the BREX system. However, unlike restriction‐modification systems, phage DNA does not appear to be cleaved or degraded by BREX, suggesting a novel mechanism of defense. Pan genomic analysis revealed that BREX and BREX‐like systems, including the distantly related Pgl system described in Streptomyces coelicolor, are widely distributed in ~10% of all sequenced microbial genomes and can be divided into six coherent subtypes in which the gene composition and order is conserved. Finally, we detected a phage family that evades the BREX defense, implying that anti‐BREX mechanisms may have evolved in some phages as part of their arms race with bacteria.
Synopsis
BREX is a novel host DNA methylation‐based defense system that protects B. cereus against a broad variety of phages. BREX‐like systems can be found in 10% of sequenced bacterial genomes.
BREX (Bacteriophage Exclusion) is a novel bacterial defense system that protects against a broad range of phages, both lytic and temperate.
The system is present in 10% of all sequenced prokaryotic genomes and appears in 6 variants (subtypes).
The system contains six genes, including ones coding for a protease, phosphatase, and methylase domain proteins.
The system blocks phage DNA replication in a mechanism still undetermined.
BREX is a novel host DNA methylation‐based defense system that protects B. cereus against a broad variety of phages. BREX‐like systems can be found in 10% of sequenced bacterial genomes.
Viperin is an interferon-induced cellular protein that is conserved in animals
. It has previously been shown to inhibit the replication of multiple viruses by producing the ribonucleotide ...3'-deoxy-3',4'-didehydro (ddh)-cytidine triphosphate (ddhCTP), which acts as a chain terminator for viral RNA polymerase
. Here we show that eukaryotic viperin originated from a clade of bacterial and archaeal proteins that protect against phage infection. Prokaryotic viperins produce a set of modified ribonucleotides that include ddhCTP, ddh-guanosine triphosphate (ddhGTP) and ddh-uridine triphosphate (ddhUTP). We further show that prokaryotic viperins protect against T7 phage infection by inhibiting viral polymerase-dependent transcription, suggesting that it has an antiviral mechanism of action similar to that of animal viperin. Our results reveal a class of potential natural antiviral compounds produced by bacterial immune systems.
The Toll/interleukin-1 receptor (TIR) domain is a canonical component of animal and plant immune systems
. In plants, intracellular pathogen sensing by immune receptors triggers their TIR domains to ...generate a molecule that is a variant of cyclic ADP-ribose
. This molecule is hypothesized to mediate plant cell death through a pathway that has yet to be resolved
. TIR domains have also been shown to be involved in a bacterial anti-phage defence system called Thoeris
, but the mechanism of Thoeris defence remained unknown. Here we show that phage infection triggers Thoeris TIR-domain proteins to produce an isomer of cyclic ADP-ribose. This molecular signal activates a second protein, ThsA, which then depletes the cell of the essential molecule nicotinamide adenine dinucleotide (NAD) and leads to abortive infection and cell death. We also show that, similar to eukaryotic innate immune systems, bacterial TIR-domain proteins determine the immunological specificity to the invading pathogen. Our results describe an antiviral signalling pathway in bacteria, and suggest that the generation of intracellular signalling molecules is an ancient immunological function of TIR domains that is conserved in both plant and bacterial immunity.
Stimulator of interferon genes (STING) is a receptor in human cells that senses foreign cyclic dinucleotides that are released during bacterial infection and in endogenous cyclic GMP-AMP signalling ...during viral infection and anti-tumour immunity
. STING shares no structural homology with other known signalling proteins
, which has limited attempts at functional analysis and prevented explanation of the origin of cyclic dinucleotide signalling in mammalian innate immunity. Here we reveal functional STING homologues encoded within prokaryotic defence islands, as well as a conserved mechanism of signal activation. Crystal structures of bacterial STING define a minimal homodimeric scaffold that selectively responds to cyclic di-GMP synthesized by a neighbouring cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzyme. Bacterial STING domains couple the recognition of cyclic dinucleotides with the formation of protein filaments to drive oligomerization of TIR effector domains and rapid NAD
cleavage. We reconstruct the evolutionary events that followed the acquisition of STING into metazoan innate immunity, and determine the structure of a full-length TIR-STING fusion from the Pacific oyster Crassostrea gigas. Comparative structural analysis demonstrates how metazoan-specific additions to the core STING scaffold enabled a switch from direct effector function to regulation of antiviral transcription. Together, our results explain the mechanism of STING-dependent signalling and reveal the conservation of a functional cGAS-STING pathway in prokaryotic defence against bacteriophages.
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