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Nature Reviews. Microbiology May 2022Clostridioides difficile is a Gram-positive anaerobe that can cause a spectrum of disorders that range in severity from mild diarrhoea to fulminant colitis and/or death.... (Review)
Review
Clostridioides difficile is a Gram-positive anaerobe that can cause a spectrum of disorders that range in severity from mild diarrhoea to fulminant colitis and/or death. The bacterium produces up to three toxins, which are considered the major virulence factors in C. difficile infection. These toxins promote inflammation, tissue damage and diarrhoea. In this Review, we highlight recent biochemical and structural advances in our understanding of the mechanisms that govern host-toxin interactions. Understanding how C. difficile toxins affect the host forms a foundation for developing novel strategies for treatment and prevention of C. difficile infection.
Topics: Antitoxins; Bacterial Proteins; Bacterial Toxins; Clostridioides difficile; Diarrhea; Humans
PubMed: 34837014
DOI: 10.1038/s41579-021-00660-2 -
Nature Dec 2022Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages. Similar to how eukaryotic innate immune systems...
Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages. Similar to how eukaryotic innate immune systems sense foreign invaders through pathogen-associated molecular patterns (PAMPs), many bacterial immune systems that respond to bacteriophage infection require phage-specific triggers to be activated. However, the identities of such triggers and the sensing mechanisms remain largely unknown. Here we identify and investigate the anti-phage function of CapRel, a fused toxin-antitoxin system that protects Escherichia coli against diverse phages. Using genetic, biochemical and structural analyses, we demonstrate that the C-terminal domain of CapRel regulates the toxic N-terminal region, serving as both antitoxin and phage infection sensor. Following infection by certain phages, newly synthesized major capsid protein binds directly to the C-terminal domain of CapRel to relieve autoinhibition, enabling the toxin domain to pyrophosphorylate tRNAs, which blocks translation to restrict viral infection. Collectively, our results reveal the molecular mechanism by which a bacterial immune system directly senses a conserved, essential component of phages, suggesting a PAMP-like sensing model for toxin-antitoxin-mediated innate immunity in bacteria. We provide evidence that CapRels and their phage-encoded triggers are engaged in a 'Red Queen conflict', revealing a new front in the intense coevolutionary battle between phages and bacteria. Given that capsid proteins of some eukaryotic viruses are known to stimulate innate immune signalling in mammalian hosts, our results reveal a deeply conserved facet of immunity.
Topics: Animals; Antitoxins; Bacteriophages; Capsid Proteins; Escherichia coli; Eukaryota; Pathogen-Associated Molecular Pattern Molecules; Immunity, Innate
PubMed: 36385533
DOI: 10.1038/s41586-022-05444-z -
Ugeskrift For Laeger Aug 2020Snakebite envenoming is a neglected tropical disease killing more than 100,000 people every year. Reducing the mortality and morbidity of snakebite envenoming depends on... (Review)
Review
Snakebite envenoming is a neglected tropical disease killing more than 100,000 people every year. Reducing the mortality and morbidity of snakebite envenoming depends on the accessibility of healthcare and antivenom, but also on sufficient knowledge on correct first aid treatment. In this review, we summarise the indications for antivenom treatment and which first-aid measures have proven effective, and which methods should be avoided, since many traditional methods of first-aid treatment of snakebites have been proven to be ineffective or even harmful.
Topics: Antivenins; Humans; Snake Bites
PubMed: 32800051
DOI: No ID Found -
BMJ (Clinical Research Ed.) Jan 2022
Review
Topics: Antivenins; Humans; Practice Guidelines as Topic; Primary Health Care; Snake Bites
PubMed: 34996773
DOI: 10.1136/bmj-2020-057926 -
BMB Reports Dec 2020Bacterial endoribonuclease toxins belong to a protein family that inhibits bacterial growth by degrading mRNA or rRNA sequences. The toxin genes are organized in pairs... (Review)
Review
Bacterial endoribonuclease toxins belong to a protein family that inhibits bacterial growth by degrading mRNA or rRNA sequences. The toxin genes are organized in pairs with its cognate antitoxins in the chromosome and thus the activities of the toxins are antagonized by antitoxin proteins or RNAs during active translation. In response to a variety of cellular stresses, the endoribonuclease toxins appear to be released from antitoxin molecules via proteolytic cleavage of antitoxin proteins or preferential degradation of antitoxin RNAs and cleave a diverse range of mRNA or rRNA sequences in a sequence-specific or codon-specific manner, resulting in various biological phenomena such as antibiotic tolerance and persister cell formation. Given that substrate specificity of each endoribonuclease toxin is determined by its structure and the composition of active site residues, we summarize the biology, structure, and substrate specificity of the updated bacterial endoribonuclease toxins. [BMB Reports 2020; 53(12): 611-621].
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; Endoribonucleases; Gene Expression Regulation, Bacterial; RNA, Messenger; Substrate Specificity
PubMed: 33148377
DOI: 10.5483/BMBRep.2020.53.12.203 -
Frontiers in Cellular and Infection... 2021The dynamic host environment presents a significant hurdle that pathogenic bacteria must overcome to survive and cause diseases. Consequently, these organisms have... (Review)
Review
The dynamic host environment presents a significant hurdle that pathogenic bacteria must overcome to survive and cause diseases. Consequently, these organisms have evolved molecular mechanisms to facilitate adaptation to environmental changes within the infected host. Small RNAs (sRNAs) have been implicated as critical regulators of numerous pathways and systems in pathogenic bacteria, including that of bacterial Toxin-Antitoxin (TA) systems. TA systems are typically composed of two factors, a stable toxin, and a labile antitoxin which functions to protect against the potentially deleterious activity of the associated toxin. Of the six classes of bacterial TA systems characterized to date, the toxin component is always a protein. Type I and Type III TA systems are unique in that the antitoxin in these systems is an RNA molecule, whereas the antitoxin in all other TA systems is a protein. Though hotly debated, the involvement of TA systems in bacterial physiology is recognized by several studies, with the Type II TA system being the most extensively studied to date. This review focuses on RNA-regulated TA systems, highlighting the role of Type I and Type III TA systems in several pathogenic bacteria.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; RNA; Toxin-Antitoxin Systems
PubMed: 34084755
DOI: 10.3389/fcimb.2021.661026 -
Cell Reports Dec 2022Temperate phages dynamically switch between lysis and lysogeny in their full life cycle. Some Bacillus-infecting phages utilize a quorum-sensing-like intercellular...
Temperate phages dynamically switch between lysis and lysogeny in their full life cycle. Some Bacillus-infecting phages utilize a quorum-sensing-like intercellular communication system, the "arbitrium," to mediate lysis-lysogeny decisions. However, whether additional factors participate in the arbitrium signaling pathway remains largely elusive. Here, we find that the arbitrium signal induces the expression of a functionally conserved operon downstream of the arbitrium module in SPbeta-like phages. SPbeta yopM and yopR (as well as phi3T phi3T_93 and phi3T_97) in the operon play roles in suppressing phage lytic propagation and promoting lysogeny, respectively. We further focus on phi3T_93 and demonstrate that it directly binds antitoxin MazE in the host MazF/MazE toxin-antitoxin (TA) module and facilitates the activation of MazF's toxicity, which is required for phage suppression. These findings show events regulated by the arbitrium system and shed light on how the interplay between phages and the host TA module affects phage-host co-survival.
Topics: Antitoxins; Bacteriophages
PubMed: 36476854
DOI: 10.1016/j.celrep.2022.111752 -
Journal of Bacteriology Mar 2020Type II toxin-antitoxin (TA) systems are small genetic elements composed of a toxic protein and its cognate antitoxin protein, the latter counteracting the toxicity of... (Review)
Review
Type II toxin-antitoxin (TA) systems are small genetic elements composed of a toxic protein and its cognate antitoxin protein, the latter counteracting the toxicity of the former. While TA systems were initially discovered on plasmids, functioning as addiction modules through a phenomenon called postsegregational killing, they were later shown to be massively present in bacterial chromosomes, often in association with mobile genetic elements. Extensive research has been conducted in recent decades to better understand the physiological roles of these chromosomally encoded modules and to characterize the conditions leading to their activation. The diversity of their proposed roles, ranging from genomic stabilization and abortive phage infection to stress modulation and antibiotic persistence, in conjunction with the poor understanding of TA system regulation, resulted in the generation of simplistic models, often refuted by contradictory results. This review provides an epistemological and critical retrospective on TA modules and highlights fundamental questions concerning their roles and regulations that still remain unanswered.
Topics: Antitoxins; Bacterial Toxins; Biological Evolution; Genetic Association Studies; Genome, Bacterial; Phenotype; Toxin-Antitoxin Systems
PubMed: 31932311
DOI: 10.1128/JB.00763-19 -
Toxins Dec 2022Botulism is a low incidence but potentially fatal infectious disease caused by neurotoxins produced mainly by . There are different routes of acquisition, food-borne and...
BACKGROUND
Botulism is a low incidence but potentially fatal infectious disease caused by neurotoxins produced mainly by . There are different routes of acquisition, food-borne and infant/intestinal being the most frequent presentation, and antitoxin is the treatment of choice in all cases. In Spain, botulism is under surveillance, and case reporting is mandatory.
METHODS
This retrospective study attempts to provide a more complete picture of the epidemiology of botulism in Spain from 1997 to 2019 and an assessment of the treatment, including the relationship between a delay in antitoxin administration and the length of hospitalization using the Cox proportional hazards test and Kruskal-Wallis test, and an approach to the frequency of adverse events, issues for which no previous national data have been published.
RESULTS
Eight of the 44 outbreaks were associated with contaminated commercial foods involving ≤7 cases/outbreak; preserved vegetables were the main source of infection, followed by fish products; early antitoxin administration significantly reduces the hospital stay, and adverse reactions to the antitoxin affect around 3% of treated cases.
Topics: Animals; Botulism; Antitoxins; Retrospective Studies; Spain; Clostridium botulinum; Botulinum Antitoxin
PubMed: 36668823
DOI: 10.3390/toxins15010002 -
Microbiological Research Nov 2022Toxin-antitoxin (TA) systems, composed of a stable toxin and a cognate unstable antitoxin, are ubiquitous in the genomes of bacteria and archaea. Under suitable growth... (Review)
Review
Toxin-antitoxin (TA) systems, composed of a stable toxin and a cognate unstable antitoxin, are ubiquitous in the genomes of bacteria and archaea. Under suitable growth conditions, an antitoxin prevents its cognate toxin from inducing toxicity; nonetheless, under stress or plasmid loss, it is either rapidly degraded or downregulated, thereby freeing the toxin to exert its activity toward various targets. Currently, TA systems are classified into eight types based on the nature and mode of action of antitoxins. TA expression is tightly regulated at multiple levels. These systems have various biological roles, including genetic element maintenance, virulence, stress resistance, and phage inhibition. Because of the toxic property of toxins, TA systems have been exploited for biotechnological (e.g., DNA cloning, plasmid maintenance, and counterselection) and medical (e.g., antibacterial drugs, antivirals, and anticancer therapies) applications. Herein, we provided an updated overview of TA systems by focusing on their classification, biological roles, and applications. We also described recent advances in research on TA systems and discussed research perspectives in this field.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Plasmids; Toxin-Antitoxin Systems
PubMed: 35969944
DOI: 10.1016/j.micres.2022.127159