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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
Fecal microbiota transplantation alters gut phage communities in a clinical trial for obesity
Background
Fecal microbiota transplantation (FMT) is a therapeutic intervention used to treat diseases associated with the gut microbiome. In the human gut microbiome, phages have been implicated in influencing human health, with successful engraftment of donor phages correlated with FMT treatment efficacy. The impact that gastrointestinal phages exert on human health has primarily been connected to their ability to modulate the bacterial communities in the gut. Nonetheless, how FMT affects recipients’ phage populations, and in turn, how this influences the gut environment, is not yet fully understood. In this study, we investigated the effects of FMT on the phageome composition of participants within the Gut Bugs Trial (GBT), a double-blind, randomized, placebo-controlled trial that investigated the efficacy of FMT in treating obesity and comorbidities in adolescents. Stool samples collected from donors at the time of treatment and recipients at four time points (i.e., baseline and 6 weeks, 12 weeks, and 26 weeks post-intervention), underwent shotgun metagenomic sequencing. Phage sequences were identified and characterized in silico to examine evidence of phage engraftment and to assess the extent of FMT-induced alterations in the recipients’ phageome composition.
Results
Donor phages engrafted stably in recipients following FMT, composing a significant proportion of their phageome for the entire course of the study (33.8 ± 1.2% in females and 33.9 ± 3.7% in males). Phage engraftment varied between donors and donor engraftment efficacy was positively correlated with their phageome alpha diversity. FMT caused a shift in recipients’ phageome toward the donors’ composition and increased phageome alpha diversity and variability over time.
Conclusions
FMT significantly altered recipients' phage and, overall, microbial populations. The increase in microbial diversity and variability is consistent with a shift in microbial population dynamics. This proposes that phages play a critical role in modulating the gut environment and suggests novel approaches to understanding the efficacy of FMT in altering the recipient’s microbiome.
Trial registration
The Gut Bugs Trial was registered with the Australian New Zealand Clinical Trials Registry (ACTR N12615001351505). Trial protocol: the trial protocol is available at
https://bmjopen.bmj.com/content/9/4/e026174
.
A4HmAXiKAUhp3nsywzn7_Q
Video Abstract
Journal Article
The living medicine : the life-saving cure we nearly lost and why it will rescue us when antibiotics fail
The fascinating and dramatic story of a forgotten, life-saving cure to conquer deadly bacterial infections - bacteriophages - and the remarkable scientists behind them.
BOOK
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
Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study
Background
Autism spectrum disorders (ASD) are complex neurobiological disorders that impair social interactions and communication and lead to restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. The causes of these disorders remain poorly understood, but gut microbiota, the 10
13
bacteria in the human intestines, have been implicated because children with ASD often suffer gastrointestinal (GI) problems that correlate with ASD severity. Several previous studies have reported abnormal gut bacteria in children with ASD. The gut microbiome-ASD connection has been tested in a mouse model of ASD, where the microbiome was mechanistically linked to abnormal metabolites and behavior. Similarly, a study of children with ASD found that oral non-absorbable antibiotic treatment improved GI and ASD symptoms, albeit temporarily. Here, a small open-label clinical trial evaluated the impact of Microbiota Transfer Therapy (MTT) on gut microbiota composition and GI and ASD symptoms of 18 ASD-diagnosed children.
Results
MTT involved a 2-week antibiotic treatment, a bowel cleanse, and then an extended fecal microbiota transplant (FMT) using a high initial dose followed by daily and lower maintenance doses for 7–8 weeks. The Gastrointestinal Symptom Rating Scale revealed an approximately 80% reduction of GI symptoms at the end of treatment, including significant improvements in symptoms of constipation, diarrhea, indigestion, and abdominal pain. Improvements persisted 8 weeks after treatment. Similarly, clinical assessments showed that behavioral ASD symptoms improved significantly and remained improved 8 weeks after treatment ended. Bacterial and phagedeep sequencing analyses revealed successful partial engraftment of donor microbiota and beneficial changes in the gut environment. Specifically, overall bacterial diversity and the abundance of
Bifidobacterium
,
Prevotella
, and
Desulfovibrio
among other taxa increased following MTT, and these changes persisted after treatment stopped (followed for 8 weeks).
Conclusions
This exploratory, extended-duration treatment protocol thus appears to be a promising approach to alter the gut microbiome and virome and improve GI and behavioral symptoms of ASD. Improvements in GI symptoms, ASD symptoms, and the microbiome all persisted for at least 8 weeks after treatment ended, suggesting a long-term impact.
Trial registration
This trial was registered on the ClinicalTrials.gov, with the registration number
NCT02504554
Journal Article