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"Bacteriophages"
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The good virus : the untold story of phages: the most abundant life forms on Earth and what they can do for us
\"The untold story of the most abundant form of life on Earth, bacteriophages, and how they play a crucial role in our lives, our health and the health of our planet. Not all viruses are out to get us - in fact, the viruses that do us harm are vastly outnumbered by viruses that can actually save lives. At every moment, within your body and all around you, trillions of microscopic combatants are fighting an invisible war. Countless times per second, 'good' viruses known as phages are infecting and destroying bacteria. These phages are the most abundant life form on the planet and have an incredible power to heal rather than harm. So why have most of us never even heard of them? The Good Virus reveals how personalities, power and politics have repeatedly crashed together to hinder our understanding of these weird and wonderful life forms. We explore why Stalin's Soviet Union embraced using phages to fight disease but the rest of the world shunned the idea. We find out why scientists only recently realised phages are central to all ecosystems on Earth. And we meet the often eccentric phage heroes who have shaped the strange history of this field and are unlocking its exciting future. Faced with the threat of antibiotic-resistance, we need phages now more than ever. The Good Virus celebrates what phages could do for us and our planet if they are at last given the attention they deserve.\"--Publisher's description.
Book
Bacteriophage adhering to mucus provide a non-host-derived immunity
Mucosal surfaces are a main entry point for pathogens and the principal sites of defense against infection. Both bacteria and phage are associated with this mucus. Here we show that phageto-bacteria ratios were increased, relative to the adjacent environment on all mucosal surfaces sampled, ranging from cnidarians to humans. In vitro studies of tissue culture cells with and without surface mucus demonstrated that this increase in phage abundance is mucus dependent and protects the underlying epithelium from bacterial infection. Enrichment of phage in mucus occurs via binding interactions between mucin glycoproteins and Ig-like protein domains exposed on phage capsids. In particular, phage Ig-like domains bind variable glycan residues that coat the mucin glycoprotein component of mucus. Metagenomic analysis found these Ig-like proteins present in the phages sampled from many environments, particularly from locations adjacent to mucosal surfaces. Based on these observations, we present the bacteriophage adherence to mucus model that provides a ubiquitous, but non-host-derived, immunity applicable to mucosal surfaces. The model suggests that metazoan mucosal surfaces and phage coevolve to maintain phage adherence. This benefits the metazoan host by limiting mucosal bacteria, and benefits the phage through more frequent interactions with bacterial hosts. The relationships shown here suggest a symbiotic relationship between phage and metazoan hosts that provides a previously unrecognized antimicrobial defense that actively protects mucosal surfaces.
Journal Article
Statistical structure of host—phage interactions
Interactions between bacteria and the viruses that infect them (i.e., phages) have profound effects on biological processes, but despite their importance, little is known on the general structure of infection and resistance between most phages and bacteria. For example, are bacteria–phage communities characterized by complex patterns of overlapping exploitation networks, do they conform to a more ordered general pattern across all communities, or are they idiosyncratic and hard to predict from one ecosystem to the next? To answer these questions, we collect and present a detailed metaanalysis of 38 laboratory-verified studies of host–phage interactions representing almost 12,000 distinct experimental infection assays across a broad spectrum of taxa, habitat, and mode of selection. In so doing, we present evidence that currently available host–phage infection networks are statistically different from random networks and that they possess a characteristic nested structure. This nested structure is typified by the finding that hard to infect bacteria are infected by generalist phages (and not specialist phages) and that easy to infect bacteria are infected by generalist and specialist phages. Moreover, we find that currently available host–phage infection networks do not typically possess a modular structure. We explore possible underlying mechanisms and significance of the observed nested host–phage interaction structure. In addition, given that most of the available host–phage infection networks examined here are composed of taxa separated by short phylogenetic distances, we propose that the lack of modularity is a scale-dependent effect, and then, we describe experimental studies to test whether modular patterns exist at macroevolutionary scales.
Journal Article
A system for the continuous directed evolution of biomolecules
Speedy route to new biomolecules
Many biomolecules with useful properties have been generated by laboratory molecular evolution experiments, but the processes typically take days and require frequent human intervention. Esvelt
et al
. now describe a phage-assisted continuous evolution system that enables the continuous, directed evolution of gene-encoded molecules that can be linked to protein production in
Escherichia coli
. Dozens of rounds of evolution can occur in a single day using this method, as demonstrated by the evolution of novel types of T7 RNA polymerase.
Laboratory evolution has generated many biomolecules with desired properties, but a single round of mutation, gene expression, screening or selection, and replication typically requires days or longer with frequent human intervention
1
. Because evolutionary success is dependent on the total number of rounds performed
2
, a means of performing laboratory evolution continuously and rapidly could dramatically enhance its effectiveness
3
. Although researchers have accelerated individual steps in the evolutionary cycle
4
,
5
,
6
,
7
,
8
,
9
, the only previous example of continuous directed evolution was the landmark study of Wright and Joyce
10
, who continuously evolved RNA ligase ribozymes with an
in vitro
replication cycle that unfortunately cannot be easily adapted to other biomolecules. Here we describe a system that enables the continuous directed evolution of gene-encoded molecules that can be linked to protein production in
Escherichia coli
. During phage-assisted continuous evolution (PACE), evolving genes are transferred from host cell to host cell through a modified bacteriophage life cycle in a manner that is dependent on the activity of interest. Dozens of rounds of evolution can occur in a single day of PACE without human intervention. Using PACE, we evolved T7 RNA polymerase (RNAP) variants that recognize a distinct promoter, initiate transcripts with ATP instead of GTP, and initiate transcripts with CTP. In one example, PACE executed 200 rounds of protein evolution over the course of 8 days. Starting from undetectable activity levels in two of these cases, enzymes with each of the three target activities emerged in less than 1 week of PACE. In all three cases, PACE-evolved polymerase activities exceeded or were comparable to that of the wild-type T7 RNAP on its wild-type promoter, representing improvements of up to several hundred-fold. By greatly accelerating laboratory evolution, PACE may provide solutions to otherwise intractable directed evolution problems and address novel questions about molecular evolution.
Journal Article
Standardized bacteriophage purification for personalized phage therapy
The world is on the cusp of a post-antibiotic era, but researchers and medical doctors have found a way forward—by looking back at how infections were treated before the advent of antibiotics, namely using phage therapy. Although bacteriophages (phages) continue to lack drug approval in Western medicine, an increasing number of patients are being treated on an expanded-access emergency investigational new drug basis. To streamline the production of high-quality and clinically safe phage preparations, we developed a systematic procedure for medicinal phage isolation, liter-scale cultivation, concentration and purification. The 16- to 21-day procedure described in this protocol uses a combination of modified classic techniques, modern membrane filtration processes and no organic solvents to yield on average 23 mL of 10
11
plaque-forming units (PFUs) per milliliter for
Pseudomonas
,
Klebsiella
, and
Serratia
phages tested. Thus, a single production run can produce up to 64,000 treatment doses at 10
9
PFUs, which would be sufficient for most expanded-access phage therapy cases and potentially for clinical phase I/II applications. The protocol focuses on removing endotoxins early by conducting multiple low-speed centrifugations, microfiltration, and cross-flow ultrafiltration, which reduced endotoxins by up to 10
6
-fold in phage preparations. Implementation of a standardized phage cultivation and purification across research laboratories participating in phage production for expanded-access phage therapy might be pivotal to reintroduce phage therapy to Western medicine.
This protocol provides standardized laboratory manufacturing practices to select, cultivate and purify bacteriophages for human clinical applications. The procedure covers all stages from phage isolation and characterization to quality control.
Journal Article
Clades of huge phages from across Earth’s ecosystems
Bacteriophages typically have small genomes
1
and depend on their bacterial hosts for replication
2
. Here we sequenced DNA from diverse ecosystems and found hundreds of phage genomes with lengths of more than 200 kilobases (kb), including a genome of 735 kb, which is—to our knowledge—the largest phage genome to be described to date. Thirty-five genomes were manually curated to completion (circular and no gaps). Expanded genetic repertoires include diverse and previously undescribed CRISPR–Cas systems, transfer RNAs (tRNAs), tRNA synthetases, tRNA-modification enzymes, translation-initiation and elongation factors, and ribosomal proteins. The CRISPR–Cas systems of phages have the capacity to silence host transcription factors and translational genes, potentially as part of a larger interaction network that intercepts translation to redirect biosynthesis to phage-encoded functions. In addition, some phages may repurpose bacterial CRISPR–Cas systems to eliminate competing phages. We phylogenetically define the major clades of huge phages from human and other animal microbiomes, as well as from oceans, lakes, sediments, soils and the built environment. We conclude that the large gene inventories of huge phages reflect a conserved biological strategy, and that the phages are distributed across a broad bacterial host range and across Earth’s ecosystems.
Genomic analyses of major clades of huge phages sampled from across Earth’s ecosystems show that they have diverse genetic inventories, including a variety of CRISPR–Cas systems and translation-relevant genes.
Journal Article
Phage Display Technique as a Tool for Diagnosis and Antibody Selection for Coronaviruses
Phage display is one of the important and effective molecular biology techniques and has remained indispensable for research community since its discovery in the year 1985. As a large number of nucleotide fragments may be cloned into the phage genome, a phage library may harbour millions or sometimes billions of unique and distinctive displayed peptide ligands. The ligand–receptor interactions forming the basis of phage display have been well utilized in epitope mapping and antigen presentation on the surface of bacteriophages for screening novel vaccine candidates by using affinity selection-based strategy called biopanning. This versatile technique has been modified tremendously over last three decades, leading to generation of different platforms for combinatorial peptide display. The translation of new diagnostic tools thus developed has been used in situations arising due to pathogenic microbes, including bacteria and deadly viruses, such as Zika, Ebola, Hendra, Nipah, Hanta, MERS and SARS. In the current situation of pandemic of Coronavirus disease (COVID-19), a search for neutralizing antibodies is motivating the researchers to find therapeutic candidates against novel SARS-CoV-2. As phage display is an important technique for antibody selection, this review presents a concise summary of the very recent applications of phage display technique with a special reference to progress in diagnostics and therapeutics for coronavirus diseases. Hopefully, this technique can complement studies on host–pathogen interactions and assist novel strategies of drug discovery for coronaviruses.
Journal Article
Two virulent Vibrio campbellii phages with potential for phage therapy in aquaculture
Background
As aquaculture continues to expand globally, diseases caused by
Vibrio
species are becoming increasingly prevalent. Vibriosis encompasses a range of infections, which can lead to symptoms such as skin lesions, hemorrhaging, and high mortality rates in fish and shellfish, especially in high-density farming systems, resulting in significant economic losses. Simultaneously, the extensive use of antibiotics has fostered the emergence of antibiotic-resistant bacteria, exacerbated disease outbreaks, and complicated control measures. Phage therapy, which leverages bacteriophages as natural antibacterial agents, offers a promising eco-friendly alternative to the antibiotics used in aquaculture. This study aimed to evaluate the potential of two vibriophages for phage therapy in aquaculture.
Results
Two virulent vibriophages, vB_VcaP_R24D and vB_VcaP_R25D, were isolated from aquaculture wastewater from seafood markets using
Vibrio campbellii
LMG 11216
T
as the host strain. The two vibriophages were identified based on their morphology, infection dynamics, host range, genomic features, lytic activity, and environmental stability. Both phages belong to the podovirus morphotype and exhibit a lytic life cycle characterised by a short latent period (< 10 min). Genomic analyses confirmed the absence of lysogenic genes, virulence factors, and antibiotic-resistance genes, thereby ensuring genetic safety. Additionally, both phages demonstrated high stability over a broad range of temperatures (4–45 °C) and pH (3–10). Lytic curve analyses further indicated a robust lytic efficiency during the logarithmic growth phase of the vibriophages.
Conclusions
These biological and genomic characteristics highlight the potential of vB_VcaP_R24D and vB_VcaP_R25D as effective biocontrol agents for mitigating vibriosis in aquaculture. Although this study demonstrates their narrow host range, the possibility of phage infection in other untested hosts cannot be entirely excluded. Furthermore, the findings offer valuable insights for future research on phage-host interactions and the development of phage cocktails to improve disease management in aquaculture systems.
Journal Article