Posts Tagged ‘Bacteriophages’
Whenever I write about phage therapy – using bacteriophages to treat bacterial infections – readers get overly enthusiastic about injecting patients with phages to produce a miracle cure. Look at it this way – that hasn’t worked for the last 100 years and it’s not likely to suddenly start working now. This short review is worth reading because it takes a much more thoughtful and holistic approach to the idea of phage therapy than the simple minded “phage as wonder cure” idea.
Exploiting gut bacteriophages for human health. Trends Microbiol. 20 Mar 2014 pii: S0966-842X(14)00045-6. doi: 10.1016/j.tim.2014.02.010
The human gut contains approximately 1015 bacteriophages (the ‘phageome’), probably the richest concentration of biological entities on earth. Mining and exploiting these potential ‘agents of change’ is an attractive prospect. For many years, phages have been used to treat bacterial infections in humans and more recently have been approved to reduce pathogens in the food chain. Phages have also been studied as drug or vaccine delivery vectors to help treat and prevent diseases such as cancer and chronic neurodegenerative conditions. Individual phageomes vary depending on age and health, thus providing a useful biomarker of human health as well as suggesting potential interventions targeted at the gut microbiota.
The incorporation of host DNA into phage genomes occurs across diverse bacteria, and acquisition of bacterial genes facilitates phage evolution. Although small, phage genomes have a high proportion of coding sequence relative to their size. The extent by which virus genomes can increase is constrained physically by the dimensions of their virion particles in which their DNA is packaged, by fitness costs associated with phage production, and by their packaging strategy. Although genetic material can be acquired via transduction and during DNA packaging, phage genomes are considered to be highly reduced and non-beneficial genes are lost through selective evolution. Therefore, discoveries of bacterial gene homologs in addition to the “core” phage genome are interesting, as is the diverse nature of these host associated genes.
Clostridium difficile is a major pathogen in healthcare settings, causing antibiotic associated diarrheal disease which can be fatal. Novel strains continue to emerge in clinical settings, and potential reservoirs of the bacterium include asymptomatic humans, wild and domesticated animals, and the natural environment. C. difficile pathogenicity can also be altered by the differential expression of their virulence genes, controlled via quorum sensing (QS) which is a form of bacterial communication. Through quorum sensing, cells communicate to the surrounding population via the release and detection of signalling molecules which elicit a physiological response. This paper describes the discivery of homologs of QS genes in a phage of C. difficile.
While the action and consequences of these phage QS genes is unclear, their presence and transcription during infection in a lysogenic and lytic background presents an exciting method by which phages can manipulate their hosts.
What Does the Talking?: Quorum Sensing Signalling Genes Discovered in a Bacteriophage Genome. (2014) PLoS ONE 9(1): e85131. doi:10.1371/journal.pone.0085131
The transfer of novel genetic material into the genomes of bacterial viruses (phages) has been widely documented in several host-phage systems. Bacterial genes are incorporated into the phage genome and, if retained, subsequently evolve within them. The expression of these phage genes can subvert or bolster bacterial processes, including altering bacterial pathogenicity. The phage phiCDHM1 infects Clostridium difficile, a pathogenic bacterium that causes nosocomial infections and is associated with antibiotic treatment. Genome sequencing and annotation of phiCDHM1 shows that despite being closely related to other C. difficile myoviruses, it has several genes that have not been previously reported in any phage genomes. Notably, these include three homologs of bacterial genes from the accessory gene regulator (agr) quorum sensing (QS) system. These are; a pre-peptide (AgrD) of an autoinducing peptide (AIP), an enzyme which processes the pre-peptide (AgrB) and a histidine kinase (AgrC) that detects the AIP to activate a response regulator. Phylogenetic analysis of the phage and C. difficile agr genes revealed that there are three types of agr loci in this species. We propose that the phage genes belonging to a third type, agr3, and have been horizontally transferred from the host. AgrB and AgrC are transcribed during the infection of two different strains. In addition, the phage agrC appears not to be confined to the phiCDHM1 genome as it was detected in genetically distinct C. difficile strains. The discovery of QS gene homologs in a phage genome presents a novel way in which phages could influence their bacterial hosts, or neighbouring bacterial populations. This is the first time that these QS genes have been reported in a phage genome and their distribution both in C. difficile and phage genomes suggests that the agr3 locus undergoes horizontal gene transfer within this species.
MicrobiologyBytes Weekly – timebombs, smarter antibiotic use and bacteriophages you’ve never even heard ofThursday, October 24th, 2013
In this week’s edition:
- Today is World Polio Day
- Antibiotics – have we got it all wrong?
- Unexploded device? The vCJD timebomb
- How science works
- The wonderful world of archaeal viruses
|Today (October 24th) is World Polio Day
In support of this event the UK Society for General Microbiology has published a useful document describing the fight against this disease – past, present and future – and the lessons it hold for other infections (free, and very useful for teachers and students).
|When the Most Potent Combination of Antibiotics Selects for the Greatest Bacterial Load
Cancer is a difficult disease to treat, but great advances have been made in the past few decades, mostly coming from using drugs in combination rather than one at a time. Exactly the same drug combination approach works for HIV infection, although sadly it doesn’t provide a cure. As it becomes harder and harder to treat bacterial infections with the few remaining antibiotics which are still effective, we need similarly imaginative approaches to therapy. A new paper in PLOS Biology looks at combinations of different drugs that are purposefully used to produce potent therapies. Textbook orthodoxy in medicine and pharmacology states one should hit the pathogen hard with the drug and then prolong the treatment to be certain of clearing it from the host. If the textbooks are correct, a combination of two antibiotics that prevents bacterial growth more than if just one drug were used should provide a better treatment strategy. Testing alternatives like these, however, is difficult to do in vivo or in the clinic, so the authors examined these ideas in laboratory conditions where treatments can be carefully controlled and the optimal combination therapy easily determined by measuring bacterial densities at every moment for each treatment trialled. Studying drug concentrations where antibiotic synergy can be guaranteed, they found that treatment duration was crucial. The most potent combination therapy on day 1 turned out to be the worst of all the therapies we tested by the middle of day 2, and by day 5 it barely inhibited bacterial growth; by contrast, the drugs did continue to impair growth if administered individually.
When the Most Potent Combination of Antibiotics Selects for the Greatest Bacterial Load: The Smile-Frown Transition. (2013) PLoS Biol 11(4): e1001540.
|Unexploded device? The vCJD timebomb
Over at the Principles of Molecular Virology blog, I’m publishing the updated content for the next edition of the book as I research it. Chapter 8 of Principles of Molecular Virology discusses subviral agents – viroids and prions responsible for diseases such as scrapie, BSE and CJD. So many facts about human prion disease remain unknown, but what is clear is that decades after it started, mad cow disease has not gone away – the effects of the outbreak will rumble on for decades to come. New data from the UK show that the previous estimate of the number of vCJD carriers was an underestimate, but what does the future hold for those exposed to BSE-infected food in the 1980s and 1990s?
|Molecular structure of the HIV-1 envelope protein
A group of researchers publishes a structure for the HIV-1 envelope protein complex – the crucial membrane-fusing molecular machine responsible for virus attachment and entry into host cells and which is the sole virus-specific target for neutralizing antibodies (Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer. (2013) PNAS USA 110 (30): 12438-12443). You’d think people would be happy. But not everyone is. “You got it wrong” they say, or “Oh no it isn’t“. “We took you comments into account and we still believe we are right” say the original authors. “Look at this picture of Einstein” says the world’s leading expert in the field. This saga is a great illustration of how science really works and a warning for students and journalists who want to believe that there are simple right/wrong answers to complex questions and that we either know something or we don’t. A great example of how sciences inches closer to the truth one step at a time.
|The wonderful world of archaeal viruses
Think you know about bacteriophages? You might be shocked at how much you have to learn. Most microbiologists are obsessed with “true bacteria”, to the virtual exclusion of the Archaea. That prejudice carries over to their viruses. This review [sorry this one requires a subscription - I try to avoid this whenever I can] presents a personal account of research on archaeal viruses and describes many new virus species and families, demonstrating that viruses of Archaea constitute a distinctive part of the virosphere and display structures that are not associated with the other two domains of life, Bacteria and Eukarya. Studies of archaeal viruses provide new perspectives concerning the nature, diversity, and evolution of virus-host interactions. Broaden your outlook – this one is well worth reading.
The wonderful world of archaeal viruses. (2013) Ann Rev Microbiol. 67: 565-585.
Got any comments or questions about any of these items? Just let me know.
University of Leicester researchers use phages to fight Clostridium difficile
Since the discovery of the first antibiotic – penicillin – antibiotics have been heralded as the ‘silver bullets’ of medicine. They have saved countless lives and impacted on the well-being of humanity. This was beautifully illustrated in Michel Mosley’s TV series Pain Pus and Poison this week. But less than a century following their discovery, the future impact of antibiotics is dwindling at a pace that no one anticipated, with more and more bacteria out-smarting and ‘out-evolving’ these miracle drugs. This has re-energised the search for new treatments, such as phages. The key advantage of using phages over antibiotics lies in their specificity. A phage will infect and kill only a specific strain/species of bacteria. This is particularly important when treating conditions like C. difficile infections:
Microbial ecologists have devoted considerable effort to understanding the nature of the viruses in seawater, because viruses have key roles in the evolution, ecology and mortality of marine plankton. For at least the past two decades, researchers have assumed that the pool of viruses in the ocean is dominated by bacteriophages with DNA genomes. Perhaps as a consequence, studies of the molecular diversity of marine viruses have most commonly focused on DNA viruses. However, evidence that RNA viruses are important contributors to marine plankton ecology has been steadily accumulating.
A recent paper shows that there are a large number of RNA viruses in surface ocean waters, and concludes that RNA viruses made up between 38 and 63% of the viruses in the sea water. In other words, about half of the viruses in the ocean (or at least, off Hawaii, where such fieldwork is most fun) are RNA viruses, suggesting that our current guess at the total number of viruses on earth, 1031, could be a major under estimate.
Are we missing half of the viruses in the ocean? (2013) ISME Journal 7, 672–679 doi: 10.1038/ismej.2012.121
Viruses are abundant in the ocean and a major driving force in plankton ecology and evolution. It has been assumed that most of the viruses in seawater contain DNA and infect bacteria, but RNA-containing viruses in the ocean, which almost exclusively infect eukaryotes, have never been quantified. We compared the total mass of RNA and DNA in the viral fraction harvested from seawater and using data on the mass of nucleic acid per RNA- or DNA-containing virion, estimated the abundances of each. Our data suggest that the abundance of RNA viruses rivaled or exceeded that of DNA viruses in samples of coastal seawater. The dominant RNA viruses in the samples were marine picorna-like viruses, which have small genomes and are at or below the detection limit of common fluorescence-based counting methods. If our results are typical, this means that counts of viruses and the rate measurements that depend on them, such as viral production, are significantly underestimated by current practices. As these RNA viruses infect eukaryotes, our data imply that protists contribute more to marine viral dynamics than one might expect based on their relatively low abundance. This conclusion is a departure from the prevailing view of viruses in the ocean, but is consistent with earlier theoretical predictions.
Pelagibacter ubique is the most successful member of a group of bacteria called SAR11, that jointly constitute about a third of the single-celled organisms in the ocean. But this is not P. ubique’s only claim to fame, for unlike almost every other known cellular creature, it and its relatives have seemed to be untroubled by viruses. But four viruses that parasitise P. ubique have now neen found, and one called HTVC010P was the commonest. It thus displaces its host as the likely winner of the most-common-living-thing prize.
Abundant SAR11 viruses in the ocean. (2013) Nature. doi: 10.1038/nature11921 http://goo.gl/iXVyF
Phage and their bacterial hosts are the most abundant and genetically diverse group of organisms on the planet. Given their dominance, it is no wonder that many recent studies have found that phage-bacteria interactions strongly influence global biogeochemical cycles, incidence of human diseases, productivity of industrial microbial commodities, and patterns of microbial genome diversity. Unfortunately, given the extreme diversity and complexity of microbial communities, traditional analyses fail to characterize interaction patterns and underlying processes.
Despite increasing recognition that phages play a significant role in shaping microbial ecosystems, fundamental questions remain unanswered. Quantifying who infects whom is essential to understand how infections at the cellular level (such as changes to metabolic rates, gene transfer, and the fate of cells) scale-up to influence ecosystem function in complex environments. This paper reviews systems approaches that combine empirical data with rigorous theoretical analysis to study phage-bacterial interactions as networks rather than as coupled interactions in isolation, and highlights the ways in which a better understanding of phage–bacteria infection networks will aid predictive models of viral effects on microbial communities, from microbiomes to the whole Earth.
Molecular piracy is a biological phenomenon in which one replicon (the pirate) uses the structural proteins encoded by another replicon (the helper) to package its own genome and thus allow its propagation and spread. Such piracy is dependent on a complex web of interactions between the helper and the pirate that occur at several levels, from transcriptional control to macromolecular assembly. The best characterized examples of molecular piracy are from the E. coli P2/P4 system and the S. aureus SaPI pathogenicity island/helper system. In both of these cases, the pirate element is mobilized and packaged into phage-like transducing particles assembled from proteins supplied by a helper phage that belongs to the Caudovirales order of viruses (tailed, dsDNA bacteriophages).
This review summarizes and compares the processes that are involved in molecular piracy in these two systems.