It’s possible that I shall make an ass of myself. But in that case one can always get out of it with a little dialectic. I have, of course, so worded my proposition as to be right either way (K.Marx, Letter to F.Engels on the Indian Mutiny)
Even when passed through water treatment plants, some types of viruses can remain infectious for at least 2 days by riding on tiny plastic pellets known as microplastics, The Guardian reports. Researchers compared the survival of two types of viruses—a enveloped or lipid-coated bacteriophage virus that only infects bacteria and a nonenveloped rotavirus (pictured) that causes diarrhea and upset stomachs in humans—in three types of treated water with and without microplastics present. The lipid membrane surrounding the bacteriophage virus made it decay quickly with or without microplastics present, but the membraneless rotavirus stayed stable for the 48-hour test period when surrounded with microplastics, the scientists report this month in Environmental Pollution. The researchers posit that the rotavirus, unburdened by a lipid membrane, survived by “hitchhiking” with microplastics and flowing back into rivers and lakes, where it could be swallowed by unsuspecting people taking a dip.
Friday, June 16, 2023
New biotech venture PHIOGEN, a spinoff of BCM’s TAILOR Labs, to tackle the global threat of antimicrobial resistance
The new biotech venture PHIOGEN is a spin-off company from Baylor College of Medicine’s TAILOR Labs, one of the United States only academic phage therapy cores with a decade’s worth of revolutionary research related to bacteriophages, viruses that infect and destroy bacteria.
PHIOGEN’s R&D efforts are led by phage researcher Dr. Anthony Maresso, founder of TAILOR Labs and associate professor of molecular virology and microbiology at Baylor, whose phage therapy work has attracted funding of more than $5 million to date.
The globally renowned research team behind PHIOGEN is housed in the world’s largest medical complex inside the prestigious Texas Medical Center’s Innovation Hub.
PHIOGEN has developed a world-first technology platform that mobilizes the natural power of bacteriophages to tackle critical and life-threatening infections. This marks a significant medical breakthrough for countering the global threat of antimicrobial resistance.
The World Health Organization deems drug resistant infections as one of the top 10 global public health threats facing humanity with estimates of over 5 million deaths worldwide attributed to antibiotic resistant infections.
The proprietary first-of-its-kind technology platform that is being spearheaded by PHIOGEN is able to discover and screen at-scale naturally occurring bacteriophages, singling out those with elite bacteria-fighting abilities, and directing biological changes to evolve the phage into antimicrobials that overcome resistance.
This creates a new business model for phage therapy as the group is able to create products that treat populations of people instead of on a per patient basis. By optimizing nature’s defenders, the team has produced unprecedented phage treatments which have already successfully saved the lives of several patients in FDA approved, compassionate use cases.
“We receive high-performing phage fighters that are trained and ready to deliver safe and effective treatments for clinical applications,” said Amanda Burkardt, CEO at PHIOGEN.
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About PHIOGEN
PHIOGEN™ is a trademark of PHIOGEN INC. PHIOGEN is an innovative biotech company housed in the Texas Medical Center Innovation Hub. It is committed to using proven technology to deliver patient-ready bacteriophage products to tackle the most deadly and serious bacterial infections. PHIOGEN’s world-class patented process has received early proof of concept validation through several in vivo studies as well as for patients in FDA-approved compassionate use cases.
Learn more about the clinical successes of phage therapy in this video interview with Dr. Maresso.
Phage interactions with bacteria are well known, and interactions between bacteria and their mammalian host can lead to a range of symbioses. However, the impact of bacteriophages on mammalian cellular and immunological processes is not well understood. Now, a new study by researchers at Monash University suggests that mammalian cells internalize phages as a resource to promote cellular growth and survival.
“There is a growing appreciation that the direct interaction between bacteriophages and the mammalian host can facilitate diverse and unexplored symbioses,” wrote the researchers. “Yet the impact these bacteriophages may have on mammalian cellular and immunological processes is poorly understood. Here, we applied highly purified phage T4, free from bacterial byproducts and endotoxins to mammalian cells and analyzed the cellular responses using luciferase reporter and antibody microarray assays.”
In order to investigate how mammalian cells’ immune responses interact with and are modulated by interactions with phages, researchers led by Jeremy J. Barr, PhD, associate professor at Monash University, applied phage T4 to mammalian cells in vitro and analyzed the cellular responses using luciferase reporter and antibody microarray assays.
The researchers found that T4 phages did not activate DNA-mediated inflammatory pathways, but triggered a sequence of signaling pathway events that promote cellular growth and survival.
“Highly purified T4 phages were rapidly internalized by mammalian cells and accumulated within macropinosomes but did not activate the inflammatory DNA response TLR9 or cGAS-STING pathways,” noted the researchers. “Following 8 hours of incubation with T4 phage, whole cell lysates were analyzed via antibody microarray that detected expression and phosphorylation levels of human signaling proteins. T4 phage application led to the activation of AKT-dependent pathways, resulting in an increase in cell metabolism, survival, and actin reorganization, the last being critical for macropinocytosis and potentially regulating a positive feedback loop to drive further phage internalization.”
Future studies are needed to determine why cells use phage particles as resources, and whether they have specifically evolved via adaptation to benefit from this internalization.
According to the authors, “This preliminary study provides novel insights into the impact phages have on mammalian systems, with broader potential implications across the fields of immunology, phage therapy, microbiome, and human health.”
Barr added, “This work provides new insights into the additional benefits that bacteriophages may have on their mammalian hosts. This is of particular importance given the increased use of phage therapy to treat antibiotic-resistant infections.”
Pocillopora corals from Mo'orea. Credit: Andrew Thurber, OSU
Scientists at Oregon State University have shown that viral infection is involved in coral bleaching—the breakdown of the symbiotic relationship between corals and the algae they rely on for energy.
Funded by the National Science Foundation, the research is important because understanding the factors behind coral health is crucial to efforts to save the Earth's embattled reefs—between 2014 and 2017 alone, more than 75% experienced bleaching-level heat stress, and 30% suffered mortality-level stress.
The planet's largest and most significant structures of biological origin, coral reefs are found in less than 1% of the ocean but are home to nearly one-quarter of all known marine species. Reefs also help regulate the sea's carbon dioxide levels and are a vital hunting ground that scientists use in the search for new medicines.
Since their first appearance 425 million years ago, corals have branched into more than 1,500 species. A complex composition of dinoflagellates—including the algae symbiont—fungi, bacteria, archaea and viruses make up the coral microbiome, and shifts in microbiome composition are connected to changes in coral health.
The algae the corals need can be stressed by warming oceans to the point of dysbiosis—a collapse of the host-symbiont partnership.
To better understand how viruses contribute to making corals healthy or unhealthy, Oregon State Ph.D. candidate Adriana Messyasz and microbiology researcher Rebecca Vega Thurber of the OSU College of Science led a project that compared the viral metagenomes of coral colony pairs during a minor 2016 bleaching event in Mo'orea, French Polynesia.
Also known as environmental genomics, metagenomics refers to studying genetic material recovered directly from environmental samples, in this case samples taken from a coral reef.
For this study, scientists collected bleached and non-bleached pairs of corals to determine if the mixes of viruses on them were similar or different. The bleached and non-bleached corals shared nearly identical environmental conditions.
"After analyzing the viral metagenomes of each pair, we found that bleached corals had a higher abundance of eukaryotic viral sequences, and non-bleached corals had a higher abundance of bacteriophage sequences," Messyasz said. "This gave us the first quantitative evidence of a shift in viral assemblages between coral bleaching states."
Bacteriophage viruses infect and replicate within bacteria. Eukaryotic viruses infect non-bacterial organisms like animals.
In addition to having a greater presence of eukaryotic viruses in general, bleached corals displayed an abundance of what are called giant viruses. Known scientifically as nucleocytoplasmic large DNA viruses, or NCLDV, they are complex, double-stranded DNA viruses that can be parasitic to organisms ranging from the single-celled to large animals, including humans.
"Giant viruses have been implicated in coral bleaching," Messyasz said. "We were able to generate the first draft genome of a giant virus that might be a factor in bleaching."
The researchers used an electron microscope to identify multiple viral particle types, all reminiscent of medium- to large-sized NCLDV, she said.
"Based on what we saw under the microscope and our taxonomic annotations of viral metagenome sequences, we think the draft genome represents a novel, phylogenetically distinct member of the NCLDVs," Messyasz said. "Its closest sequenced relative is a marine flagellate-associated virus."
The new NCLDV is also present in apparently healthy corals but in far less abundance, suggesting it plays a role in the onset of bleaching and/or its severity, she added.
- We have found five new species that we believe are unknown to science, said associate professor Clare Kirkpatrick, who studies bacterial stress-response at the Department of Biochemistry and Molecular Biology at University of Southern Denmark.
The somewhat surprising discovery was made during the coronavirus pandemic, when some of Kirkpatrick's students could not carry out their normal microbe studies in the laboratory and therefore went on field trips to local creeks to see if they had any interesting microbes to offer.
The fact that viruses exist in nature is not surprising, as they are the world's most widespread organism. They are everywhere and part of all kinds of microbial cycles and ecosystems, but the fact that five potentially new species have appeared in local creeks, did surprise Clare Kirkpatrick.
While four of the five have not yet had their genome mapped in a genome sequencing, one species has now been fully sequenced, scientifically described, named and published in Microbiology Resource Announcements. The name is Fyn8.
Many viruses are so-called bacteriophages (or phages), meaning that they kill bacteria, and Fyn8 is no exception. It can attack and kill the bacteria Pseudomonas aeruginosa.
Pseudomonas aeruginosa is a bacterium found naturally in soil and water. It is normally harmless towards healthy people, but like many other bacteria it has developed resistance to antibiotics and is found in hospitals.
For example, patients with wounds (like burn patients) and ventilator patients are at risk of getting an infection that cannot be fought with antibiotics.
The researchers have no doubt that Fyn8 can effectively kill Pseudomonas aeruginosa:
- We could see it with the naked eye: Clear holes appeared in the layer of Pseudomonas aeruginosa bacteria in our petri dishes, where Fyn8 had infected the bacterial cells, killed them, multiplied and proceeded to attack the next.
Considering that the world is facing a resistance crisis, where more people will die from an infection with resistant bacteria than from cancer, the new finding is of course interesting and raises the question; Can phages help us in the fight against resistant bacteria?
Research in this field has been uncommon until recently, both in academic research institutions and in pharmaceutical companies. In the past and in other parts of the world however, there has been some research, and phages have also been used to treat infections in Eastern European countries in particular.
The phages were discovered at the beginning of the 20th century by researchers who had their bacterial cultures destroyed by virus infections.
The benefits of that discovery were obvious, but antibiotics, not phages, became the most widespread cure against bacterial infections.
One reason was perhaps that antibiotics were easy to produce and easy to use, while the phages were difficult to isolate and give to patients.
Another reason was probably also that an antibiotic dose could kill many different bacteria, while a phage only matches with a single bacterial species.
- But today it is relatively easy to make precision medicine for the individual patient. First you find out what exact bacteria a patient is infected with - and then you can treat the patient with exactly the phage that will kill the bacteria, explained Clare Kirkpatrick.
She adds that this strategy works even on bacteria which are resistant to all known antibiotics.
Time will tell whether there are more new virus species in the local creeks near University of Southern Denmark campus, but it is quite probable, Clare Kirkpatrick believes:
- Many, many more are waiting to be discovered.
Bacteria killing viruses in nature: Viruses that infect and kill bacteria are called bacteriophages. An estimated 10,000,000,000,000,000,000,000,000,000,000 (1031) of them exist in nature. That is roughly one trillion bacteriophages for every grain of sand in the world.
The threat of antibiotic resistance rises as bacteria continue to evolve to foil even the most powerful modern drug treatments. By 2050, antibiotic resistant-bacteria threaten to claim more than 10 million lives as existing therapies prove ineffective.
Bacteriophage, or "phage," have become a new source of hope against growing antibiotic resistance. Ignored for decades by western science, phages have become the subject of increasing research attention due to their capability to infect and kill bacterial threats.
A new project led by University of California San Diego Biological Sciences graduate student Joshua Borin, a member of Associate Professor Justin Meyer's laboratory, has provided evidence that phages that undergo special evolutionary training increase their capacity to subdue bacteria. Like a boxer in training ahead of a title bout, pre-trained phages demonstrated they could delay the onset of bacterial resistance.
The study, which included contributions from researchers at the University of Haifa in Israel and the University of Texas at Austin, is published June 8 in the Proceedings of the National Academy of Sciences.
"Antibiotic resistance is inherently an evolutionary problem, so this paper describes a possible new solution as we run out of antibiotic drug options," said Borin. "Using bacterial viruses that can adapt and evolve to the host bacteria that we want them to infect and kill is an old idea that is being revived. It's the idea of the enemy of our enemy is our friend."
The idea of using phages to combat bacterial infections goes back to the days prior to World War II. But as antibiotic drugs became the leading treatment for bacterial infections, phage research for therapeutic potential was largely forgotten. That mindset has changed in recent years as deadly bacteria continue to evolve to render many modern drugs ineffective.
Borin's project was designed to train specialized phage to fight bacteria before they encounter their ultimate bacterial target. The study, conducted in laboratory flasks, demonstrated classic evolutionary and adaptational mechanisms at play. The bacteria, Meyer said, predictably moved to counter the phage attack. The difference was in preparation. Phages trained for 28 days, the study showed, were able to suppress bacteria 1,000 times more effectively and three- to eight-times longer than untrained phage.
"The trained phage had already experienced ways that the bacteria would try to dodge it," said Meyer. "It had 'learned' in a genetic sense. It had already evolved mutations to help it counteract those moves that the bacteria were taking. We are using phage's own improvement algorithm, evolution by natural selection, to regain its therapeutic potential and solve the problem of bacteria evolving resistance to yet another therapy."
The researchers are now extending their findings to research how pre-trained phages perform on bacteria important in clinical settings, such as E. coli. They are also working to evaluate how well training methods work in animal models.
UC San Diego is a leader in phage research and clinical applications. In 2018 the university's School of Medicine established the Center for Innovative Phage Applications and Therapeutics, the first dedicated phage therapy center in North America.
"We have prioritized antibiotics since they were developed and now that they are becoming less and less useful people are looking back to phage to use as therapeutics," said Meyer. "More of us are looking into actually running the experiments necessary to understand the types of procedures and processes that can improve phage therapeutics."
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The study's full author list includes: Joshua Borin, Sarit Avrani, Jeffrey Barrick, Katherine Petrie and Justin Meyer.
CAPTION
Trained and untrained phages are pitted against bacteria in battleground flasks to evaluate which is more effective at killing.
Personalized phage therapy heals resistant wounds-squeaks makes full recovery
THE HEBREW UNIVERSITY OF JERUSALEM
A new study demonstrates an advance in treating antibiotic-resistant infections in animals through personalized phage therapy. The treatment combined a specific anti-P. aeruginosa phage applied topically with ceftazidime administered intramuscularly, resulting in the complete healing of a persistent surgical wound after fourteenweeks. This highlights the potential of phage therapy as a practical and effective solution for antibiotic-resistant infections in veterinary practice, with implications for human medicine as well.
A new study led by Prof. Ronen Hazan and his team, from the Faculty of Dental Medicine at the Hebrew University of Jerusalem, in collaboration with the team of Vet Holim, JVMV -Veterinary medical center in Kiryat -Anavim, Israel, has shown an advance in the treatment of antibiotic-resistant infections in animals. This research, focusing on a five-year-old Siamese cat Squeaks with a multidrug-resistant Pseudomonas aeruginosa infection post-arthrodesis surgery, marks the first published documented application of personalized phage therapy in veterinary medicine.
Squeaks, initially treated at the JVMV for injuries sustained from a high-rise fall, developed a severe infection in the right hind leg following multiple surgeries. This infection persisted despite various antibiotic treatments over four months. Facing a potential implant-replacement surgery, the team turned to the new treatment which involved a meticulously designed combination of a specific anti-P. aeruginosa phage, a virus that kills bacteria, applied topically to the surgical wound and ceftazidime administered intramuscularly. Moreover, the owners of the cat, after short demonstration, provides most of the treatment doses of phages and antibiotics at their home.
The integration of phage therapy with antibiotics was aimed at targeting the pathogen effectively and directly at the site of infection, leveraging the phage’s ability to be applied topically, which simplifies administration and maximizes its concentration at the infection site. This approach allowed the surgical wound, which had remained open for five months, to fully heal after to fourteen weeks of treatment.
The successful outcome of this case underscores the critical need for novel therapeutics like phage therapy to address the growing concern of antibiotic-resistant infections, which affect up to 8.5% of surgical sites following orthopedic surgeries in companion animals. These infections not only pose significant health risks to the animals but also increase the morbidity, mortality, and costs associated with these procedures.
Recent studies suggest that phage therapy, already showing high success rates in human medicine for treating orthopedic infections and chronically infected wounds, can offer a promising solution for similar issues in veterinary practice. Moreover, the successful treatment of this cat by its owners at home highlights the practicality and efficacy of personalized phage therapy, which could be extended to treat other pets facing similar antimicrobial resistance challenges.
Interestingly, opposite to common situations, this case was performed on an animal based on the team's insights from treating humans first.
The positive reception from veterinarians and pet owners regarding phage therapy points to a growing awareness and acceptance of this treatment option. As the new treatment continues to be explored in veterinary settings, it not only improves the health and well-being of pets but also offers valuable data that contribute to the broader application of phage therapy in both animals and humans. This bridging of data can enhance treatment protocols and outcomes across a variety of bacterial infections, potentially changing the landscape of infection treatment in both veterinary and human medicine.
Successful phage-antibiotic therapy of P. aeruginosa implant-associated infection in a Siamese cat
Phage therapy: In-depth discussion on ethical considerations and regulatory landscape at upcoming European conference “Targeting Phage Therapy 2024”
MITOCHONDRIA-MICROBIOTA TASK FORCE
The 7th World Conference on Targeting Phage Therapy 2024 is set to take place on June 20-21 at the Corinthia Palace in Malta, welcoming over 150 attendees from 30 countries and featuring more than 32 communications. This annual event showcases the latest advancements in phage research and therapy, emphasizing how these developments could revolutionize healthcare practices globally.
The Ethical Considerations and Regulatory Landscape of Phage Therapy will be highlighted
Targeting Phage Therapy 2024 will include a dedicated session on the ethical and regulatory aspects of phage therapy, particularly in Europe. Barbara Brenner, a legal expert in medical law and human rights, will deliver a talk titled "Regulatory Restrictions vs. Human Rights, the Hippocratic Oath, and the Freedom of Therapy – The Legal Aspect of Phage Therapy". Her presentation will focus on balancing regulatory frameworks with the urgent need for accessible, life-saving treatments.
Phage therapy faces significant regulatory and ethical challenges, and Brenner will address several critical points:
- Regulatory Frameworks and Human Rights: Brenner will provide an overview of EU and German legal and regulatory frameworks, highlighting the tension between the right to safe drugs and the right to life-saving treatment in emergencies, especially concerning antimicrobial-resistant (AMR) infections and non-GMP phages.
- Ethical and Legal Questions: The session will explore whether it is ethical to deny life-saving treatments for safety reasons and whether regulatory bodies like the FDA and EMA can be held liable for prohibiting non-GMP phages if GMP phages are unavailable or unaffordable. Additionally, Brenner will discuss the validity of scientific evidence derived from anecdotal sources versus the necessity of randomized controlled trials (RCTs) and whether these trials need to be redesigned. The legal status of phage therapy as "experimental" and the potential liability of clinicians who refuse phage therapy when it could save a patient will also be examined.
- Combatting Antimicrobial Resistance (AMR): The presentation will include the One Health approach, integrating human, animal, and environmental health practices. Brenner will highlight Georgia's successful model, advocating for the promotion of phages as primary interventions, reserving chemical antibiotics for situations where phages are ineffective.
Speakers Lineup
Robert T. Schooley, University of California, San Diego, USA
Clinical Trials in Phage Therapeutics: Looking Under the Hood
Ekaterina Chernevskaya, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Russia
Adaptive Phage Therapy in the Intensive Care Unit: From Science to Patients
Jean-Paul Pirnay, Queen Astrid Military Hospital, Belgium
Magistral Phage Preparations: Is This the Model for Everyone?
Barbara Brenner, Kanzlei BRENNER, Germany
Regulatory restrictions vs. Human Rights, the Hippocratic oath and the Freedom of therapy– The legal aspect ofphage therapy
Nannan Wu, Shanghai Public Health Clinical Center, Fudan University, China
Phage Therapy: A Glimpse into Clinical Studies Involving Over 150 Cases
Graham F. Hatfull, University of Pittsburgh, USA
Mycobacteriophages and Their Therapeutic Potential
Antonia P. Sagona, University of Warwick, United Kingdom
Genetic Engineering of Phages to Target Intracellular Bloodstream E.coli Infections
Paul Turner, Yale University, USA
Leveraging Evolutionary Trade-Offs in Development of Phage Therapy
Pieter-Jan Ceyssens, Sciensano, Belgium
Quality control of phage Active Pharmaceutical Ingredients (APIs) in Belgium
Wolfgang Weninger, Medical University of Vienna, Austria
The Phageome in Normal and Inflamed Human Skin
Sabrina Green, KU Leuven, Belgium
Making Antibiotics Great Again: Phage resistance in vivo correlates to resensitivity to antibiotics in pan-resistant Pseudomonas aeruginosa
Rodrigo Ibarra Chávez, University of Copenhagen, Denmark
Phage Satellites, a Diversity of Extradimensional Symbionts and Pathways to Phage Therapy
Domenico Frezza, University of Roma Tor Vergata, Italy
Towards efficient phage therapies: investigation of phage / bacteria equilibrium with metagenome of dark matter in natural samples
Besarion Lasareishvili, Eliava Institute of Bacteriophage, Microbiology and Virology, Georgia
Modern Concepts of Phage Therapy: An Immunologist’s Vision
Kilian Vogele, Invitris, Germany
Cell-Free Production of Personalized Therapeutic Phages Targeting Multidrug-Resistant Bacteria
Frederic Bertels, Max Planck Institute for Evolutionary Biology, Germany
Improving Phages through Experimental Evolution
Eugene V Koonin, National Institutes of Health, USA
Evolution and megataxonomy of viruses: the place of phages in the virosphere
Federica Briani, University of Milan, Italy
Addressing Phage Resistance to Enhance the Robustness of Phage Therapy for Pseudomonas aeruginosa Infections in People with Cystic Fibrosis
Jumpei Fujiki, University of California San Diego, USA
Phage therapy: Targeting intestinal bacterial microbiota for the treatment of liver disease