MICROVERSE

Attack and defence in the microverse

How small RNA molecules regulate viral infections of bacteria

Peer-Reviewed Publication

FRIEDRICH-SCHILLER-UNIVERSITAET JENA

 

IMAGE: 

VIEW OF A PETRI DISH WITH CHOLERA BACTERIA (VIBRIO CHOLERAE).

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CREDIT: JENS MEYER/UNIVERSITY OF JENA

Viruses need hosts. Whether it’s measles, the flu or coronavirus, viral pathogens cannot multiply or infect other organisms without the assistance of their hosts’ cellular infrastructure. However, humans are not the only ones affected by viruses: animals, plants and even microorganisms can all serve as hosts. Viruses that use bacteria as host cells are called bacteriophages (or simply “phages” for short) and are thought to be the most abundant biological entities of all. Just as the human immune system springs into action to resist a flu or coronavirus infection, bacteria do not simply allow phages to infiltrate their cellular machinery without a fight.

A research team at the University of Jena and its Cluster of Excellence “Balance of the Microverse” has examined in detail the complex interaction of attack and defence strategies when cholera-causing bacteria (Vibrio cholerae) are infected with a bacteriophage known as VP882—and discovered that tiny RNA molecules play a decisive role. The researchers’ findings have been published in the latest issue of a prestigious journal, Cell Host & Microbe.

From harmless housemate to cunning kidnapper

There are two ways in which phages can multiply after infecting bacteria: either as invisible passengers, hidden in the bacteria’s genetic material, or as cunning kidnappers, multiplying in vast numbers in bacterial cells without regard for potential losses and, ultimately, destroying the cells. Which method a phage adopts depends on whether sufficient numbers of other host cells are available in the immediate environment to provide shelter.

But how do phages determine this? “They rely on a chemical counting mechanism that bacteria use to identify other members of their species,” explains Prof. Dr Kai Papenfort of the University of Jena, who headed up the project. Known as “quorum sensing”, this method uses signal molecules that are produced by bacteria and released into their surroundings. At the same time, the bacteria monitor the concentration of these molecules using specific receptors, thereby gaining information about the size of their current population. “The phages’ trick essentially involves ‘listening in’ to this chemical communication between bacteria,” says Papenfort.

In their experiments, the Jena researchers examined what happens to the phages and bacteria once the bacteria emit their quorum sensing signals. “We have observed that 99% of bacteria are destroyed within 60 minutes, in which time the phages take control,” reports Dr Marcel Sprenger, the lead author of the article. The team discovered that this switchover is controlled by tiny RNA molecules, one of which is called “VpdS” (VP882 phage-derived sRNA). “As soon as the phages receive the chemical signal from the bacteria, this RNA is produced in high quantities,” says Sprenger.

How bacteria fight back against viruses

In order to find out precisely which genes are regulated by VpdS, the team adopted a comprehensive, technological approach and infected bacteria cultures with both VP882 phages and genetically modified phages unable to produce VpdS. Applying a method known as “RNA interaction by ligation and sequencing”, the researchers were able to identify the interactions between all RNA molecules in the bacteria cultures at different times. “This not only gave us insights into which genes are active, it also showed how they interact,” says Papenfort.

This method enabled the researchers to examine the genes of the phages as well as those of the host bacteria. As a result, the researchers gained extensive insights into the changes that occurred both during and after quorum sensing. “We were able to demonstrate that VpdS regulates phage genes as well as genes of the host, which effectively explains the destruction of bacterial cells,” says Papenfort.

However, the researchers have been able to deduce further relationships from the data they collected. For example, bacteria also have genes that, when activated by a chemical signal, fight back against the phages’ propagation and thereby counteract their own destruction. According to Papenfort, this aspect is particularly interesting. “We can see these as the precursors to the immune systems in higher organisms. Bacteria have many genes that protect them against viruses.” Given that these genes are also present in higher organisms, the researchers surmise that RNA molecules could also play an important role in their regulation.

 

Original publication:

Sprenger M. et al.: Small RNAs direct attack and defence mechanisms in a quorum sensing phage and its host. Cell. Host & Microbe (2024), https://doi.org/10.1016/j.chom.2024.03.010

 

Contact:

Prof. Dr Kai Papenfort
Institute of Microbiology at Friedrich Schiller University Jena
Winzerlaer Straße 2, 07745 Jena, Germany
Phone: +49 (0)3641 9 49311
Email: kai.papenfort@uni-jena.de

 

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JOURNAL

Cell Host & Microbe

DOI

10.1016/j.chom.2024.03.010 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Cells

ARTICLE TITLE

Small RNAs direct attack and defence mechanisms in a quorum sensing phage and its host.

ARTICLE PUBLICATION DATE

4-Apr-2024

New micromaterial releases nanoparticles that selectively destroy cancer cells

UNIVERSITAT AUTONOMA DE BARCELONA

Researchers at the Universitat Autònoma de Barcelona (UAB), in collaboration with the Sant Pau Research Institute and the CIBER-BBN, have developed micromaterials made up only of proteins, capable of delivering over an extended period of time nanoparticles that attack specific cancer cells and destroy them. The micromaterials mimic natural secretory granules found in the endocrine system and were proven effective in mouse models of colorectal cancer.

A team coordinated by Professor Antonio Villaverde from the Institute of Biotechnology and Biomedicine of the Department of Genetics and Microbiology, UAB, and with the participation of the Sant Pau Research Institute and the CIBER-BBN, has developed self-contained micromaterials made up only of proteins that are capable of delivering over an extended period of time the polypeptide that composes them. The technology used for the fabrication of these granules, patented by the researchers, is relatively simple and mimics the secretory granules of the human endocrine system. With regards to its chemical structure, it involves the coordination of ionic zinc with histidine-rich domain, an amino acid essential for living beings and therefore not toxic.
The new micromaterials developed by researchers are formed by chains of amino acids known as polypeptides, which are functional and bioavailable in the form of nanoparticles that can be released and targeted to specific types of cancer cells, for selective destruction.
The research team analyzed the molecular structure of these materials and the dynamics behind the secretion process, both in vitro and in vivo. In an animal model of CXCR4+ colorectal cancer, the system showed high performance upon subcutaneous administration, and how the released protein nanoparticles accumulated in tumor tissues.
“It is important to highlight that this accumulation is more efficient than when the protein is administered in blood. This fact offers an unexpected new way to ensure high local drug levels and better clinical efficacy, thus avoiding repeated intravenous administration regimens”, explains Professor Antonio Villaverde. "In the clinical context, the use of these materials in the treatment of colorectal cancer should largely enhance drug efficiency and patient’s comfort, while at the same time minimizing undesired side effects."
Participating in the research, conducted principally by UAB researcher Julieta M. Sánchez, were researchers from the UAB Department of Genetics and Microbiology, the UAB Institute of Biomedicine and Biotechnology (IBB-UAB), and the Oncogenesis and Antitumor Drugs team led by Professor Ramón Mangues of the Sant Pau Research Institute. Both Professor Antonio Villaverde and Professor Ramón Mangues form part of the CIBER network of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN). Also participating in the study were the Protein Production Platform (Unit 1) and the Nanotoxicology Platform (Unit 18) of the Singular Infrastructure NANBIOSIS, and funding was received through several competitive research and technology transfer projects (including PID2019 -105416RB-I00/AEI/10.13039/501100011033, PDC2022-133858-I00, PID2022-136845OB-I00, CPP2021-008946, PI21/400), as well as intramural CIBER-BBN projects (VENOM4CANCER, NANOREMOTE and NANOSCAPE).

 

 

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JOURNAL

Advanced Science

DOI

10.1002/advs.202309427 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

Structural Stabilization of Clinically Oriented Oligomeric Proteins During their Transit through Synthetic Secretory Amyloids

 BIOLOGICAL WARFARE

The value of information gathering for phages

Peer-Reviewed Publication

PNAS NEXUS

 

IMAGE: 

ILLUSTRATION OF THE COMPETITION EXPLORED IN THE PAPER, BETWEEN PHAGES WITH A FIXED BRANCHING RATIO BETWEEN LYSOGENY AND LYSIS (GREEN) AND PHAGES WHO ADJUST THIS RATIO BASED ON ENVIRONMENTAL INFORMATION (PINK). THE LATTER, WHEN INFECTING BACTERIA (BLUE) RELEASE SIGNAL MOLECULES (PURPLE), WHICH THEY CAN THEN DETECT TO OBTAIN INFORMATION ABOUT THE ENVIRONMENT.

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CREDIT: DAHAN ET AL

Phages, the viruses that infect bacteria, will pay a high growth-rate cost to access environmental information that can help them choose which lifecycle to pursue, according to a study. Yigal Meir and colleagues developed a model of a bacteria-phage system to investigate how much the viruses should be willing to invest to acquire information about their local environment. A temperate phage, once inside a bacterium, can choose one of two life cycles. In the lytic cycle, the phage turns the bacterium into a factory for additional phages, until the cell is full of phages and the bacterium bursts and dies. In the lysogenic cycle, the phage inserts its DNA into the bacterial genome. This lysogenic strategy is useful for situations where there are few proximate infection opportunities, either because there are few bacteria nearby or because all nearby bacteria are already infected with related phages. Once phage DNA is inserted into the bacterium, its progeny will also carry phage DNA, and can produce phages in the future when there are more uninfected targets available. Knowing the extent of infection opportunities can determine which lifecycle would lead to more descendants of the phage in the long run. Some phages do have means of sensing the abundance of bacteria nearby, as well as the abundance of phage infection events nearby—but these sensing abilities require genes that come at a cost to the phage. The authors theoretically investigate the “price,” in terms of lysogenic growth rate or number of phages released per burst, that phage should be willing to pay to gain environmental information. According to the authors, a lysogenic phage that has incurred a 50% growth rate penalty to access environmental information will still outcompete a phage that does not sense the abundance of nearby phages or bacteria. 

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JOURNAL

PNAS Nexus

ARTICLE TITLE

The value of information gathering in phage-bacteria warfare

ARTICLE PUBLICATION DATE

9-Jan-2024

SEE 
 https://plawiuk.blogspot.com/search?q=PHAGES
 https://plawiuk.blogspot.com/search?q=BACTERIOPHAGE
https://plawiuk.blogspot.com/search?q=PHAGE
 https://plawiuk.blogspot.com/search?q=BIOPHAGES

#BACTERIOPHAGES

Wrocław clinic uses ‘super viruses’ to battle rebellious bacteria
JOANNA JASIŃSKA MARCH 22, 2020

The therapy being pioneered in Wrocław could help end the threat posed by super-bugs.Kalbar /TFN

A pioneering institute in Wrocław is working on experimental therapy to combat antibiotic-resistant bacterial infections.

For 15 years, the Polish Academy of Sciences Phage Therapy Unit at the Institute of Immunology and Experimental Therapy’s Medical Centre has been looking for a cure for patients who have lost all hope that their ailments could be treated.

Doctor Ryszard Międzybrodzki with Anna Kabała, one of the Medical Unit's patients. Kalbar/TFN

TFN travelled to Wrocław to discover how a revolutionary therapy the clinic is working on could be the answer to an ever-mutating threats to our health.

In short, phage therapy utilises bacteriophages – bacterial viruses which attack only bacterial cells. A patient is treated with individually matched viruses, which are able to destroy different bacteria including those which are resistant to antibiotics and which cause life-threatening infections.

The Institute of Immunology and Experimental Therapy’s Medical Centre has been looking for a cure for patients who have lost all hope that their ailments could disappear.Kalbar/TFN

Professor Andrzej Górski, the institute’s director, told TFN: “Our centre treats antibiotic-resistant infections. The great problem in medicine today is that we are becoming defenceless against the bacteria that cause them.

“Although the market is big, as it is estimated that about $30 to 40 billion are spent on antibiotics annually, antibiotic resistance crisis is growing,” he continued.

With both bacteria becoming harder to kill and pharmaceutical companies finding providing newer and newer drugs unprofitable, a change in approach will be necessary.

“Our centre treats antibiotic-resistant infections. The great problem in medicine today is that we are becoming defenceless against the bacteria that cause them,” says Professor Andrzej Górski.Kalbar/TFN

“Poland has a long tradition in this sphere, because, in fact, the first attempts to use phage therapy were made soon after regaining independence,” explained the professor. Phages were first observed in 1896 in the River Ganges by Ernest Hanbury Hankin, who noticed their antibacterial properties.

The first tries at phage therapy were attempted before World War II, but the medical documentation from that time isn’t credible according to today’s requirements. After the war, research on phages in Wrocław resumed in the 1960s.

The Institute’s Medical Unit is supported by the Bacteriophage Laboratory, which stores over 600 different phages, carries out phage typing procedures, prepares the phage formulations for patients and performs some other necessary tests.

The Institute is supported by the Bacteriophage Laboratory, which stores over 600 different phages.Kalbar/TFN

Doctor Beata Weber-Dąbrowska, the principal specialist at the institute’s laboratory, said: “Phages naturally occur everywhere where bacteria are found, so even in the most extreme conditions such as hot springs, Arctic waters or the sands of the Sahara.”

To expand their collection of phages and be able to combat a wider variety of bacteria, the researchers are constantly working on obtaining new strains.

Phages, just like other viruses, are selective when it comes to which bacteria they’re effective against. The virus will attach itself to a bacteria and inject it with its own genome. The genome replaces the bacterial one and halts the infection, making the bacteria unable to reproduce.

Phages can spring up anywhere: from Artic waters to desert sands.Kalbar/TFN

The main advantage of using phage therapy is its precision. By choosing the right type of phages doctors can be sure it will attack only the bacteria they want to counter. Doctor Weber-Dąbrowska said: “It doesn't have any effect on the body (...). We all carry phages, as I said they are everywhere, so, for example, we have a very large amount of phages isolated from samples taken from patients.

“The best environment for phages is the gastrointestinal tract because there are lots of bacteria,” she added. “Therefore, phages breed wonderfully there, but mainly for those gut bacteria.”

The Institute’s Medical Unit is not a clinic. As a research centre first and foremost, they accept only a handful of cases – patients who often have been struggling with recurring infections for years and were unable to find help elsewhere.

“This is an experimental therapy. We don’t have indisputable scientific proof that it will work,” says Doctor Ryszard Międzybrodzki.Kalbar/TFN

Since the therapy is experimental and not yet officially approved by European law for common use, the requirements are very strict. So far, they have only admitted 700 patients.

Doctor Ryszard Międzybrodzki is one of the physicians working with patients from all over the world who come to the Institute. The doctor stressed: “This is an experimental therapy. We don’t have indisputable scientific proof that it will work.

“Our group of patients are in a difficult situation because they aren’t people who are suffering from the infection for the first time and decide to use phages instead of antibiotics.”

The future of the clinic remains uncertain.Kalbar/TFN

According to Polish and European law, as well as medical ethics, to attempt the therapy, doctors have to be convinced the therapy has a chance to work. During the qualification process, they carry out an extensive examination of the strains of viruses and bacteria the patient is carrying, to know what they are dealing with.

“After qualifying, the most important factors are to grow the patient’s bacteria, check if the laboratory has the corresponding bacteriophages, and prepare the phage compound. And after that we can start the therapy,” explained Doctor Międzybrodzki.

The patients suffer from a variety of infections – respiratory, urinary, genital, infected wounds – so the compound is always directly applied where it’s needed and sometimes it can be swallowed. After a while the patients' microbiology is examined once again, to find out which strains were eliminated and which reproduced.

Doctor Beata Weber-Dąbrowska, the principal specialist at the institute’s laboratory.Kalbar/TFN

As such, the treatment is always individually prepared for each case. To reinforce the cure, it is sometimes combined with antibiotics.

Anna Kabała from Wrocław is one of the institute’s patients. Ten years ago, when pregnant, she contracted the E.coli bacteria. “During these 10 years, I've exhausted all possibilities of regular treatment. I was sent from doctor to doctor, at first unaware of how serious the infection was. After years of intensive antibiotic therapy, the options for administering antibiotics in hospitals and elsewhere ended.”

For 10 years Anna had to deal with the pain in the urinary tract and even kidney infection. The long-term illness had a severe impact on her daily life. She even had strange reactions from the people around her, who would be afraid to shake her hand, even though they couldn't contract the infection from her.

We carry phages in our bodies says Doctor Beata Weber-Dąbrowska.Kalbar/TFN

Now, after year and a half of therapy, Anna is feeling much better, and most importantly, the painful symptoms of her illness are gone.

“I regret I didn’t come here earlier,” Anna said. “There are great professionals here, specialists in very difficult cases. Thanks to them, I got my life back.”

More and more patients have been healed thanks to the phage therapy and two branches of the unit opened in Kraków and Czestochowa, but its future remains uncertain. Without a proper clinical trial, it remains a therapeutic experiment and cannot be used as a fully-fledged alternative to antibiotics.

“Everything is very promising, but it's not proof in the sense of science, according to legal and scientific standards,” states Professor Górski.Kalbar/TFN

The institute’s resources, both in terms of finances and personnel, are meagre in comparison to the potential uses of their research, which could be far more than just therapy against bacteria.

“It's just a matter of a lack of resources. The clinical trial would allow the registration of the experimental therapy for general use,” stated Professor Górski.

“The bottom line is that it has great potential. We don't know yet if the phages will break through as a therapy for drug-resistant bacterial infections. It's not clear right now. Everything is very promising, but it's not proof in the sense of science, according to legal and scientific standards.”

 

Scientists uncover prophage defense mechanisms against phage attacks in mycobacteria

Experimental approach reveals Butters prophage uses a two-component system to block entry of some phages, but not others, from attacking a strain of mycobacteria related to infection-causing strains; important for advancing phage therapies

LEHIGH UNIVERSITY

Research News

 

IMAGE: VASSIE WARE IS A PROFESSOR IN LEHIGH UNIVERSITY'S DEPARTMENT OF BIOLOGICAL SCIENCES AND IS CO-DIRECTOR OF LEHIGH'S HOWARD HUGHES MEDICAL INSTITUTION (HHMI) BIOSCIENCE PROGRAM AND DISTANCE EDUCATION PROGRAM... view more 

CREDIT: LEHIGH UNIVERSITY

A phage is a virus that invades a bacterial cell. While harmless to human cells, phages are potentially deadly to bacteria since many phages enter a cell in order to hijack its machinery in order to reproduce itself, thus destroying the cell.

While this is bad news for bacteria, it may be good news for humans. There is a growing need to develop new treatments that effectively attack deadly strains of bacteria that have become resistant to other medicines. Already used with success in some parts of the world, phage therapy is gaining traction as a more widespread way to fight antibiotic-resistant bacterial infections and even, at some point, some viral infections including, according to a recent article, possibly COVID-19.

Among the challenges: a virus type known as a prophage. A phage enters a bacterial cell and, instead of destroying it, takes up residence. Called a "prophage," it fights off other viruses' attempts to invade. According to Vassie Ware, a professor in Lehigh University's Department of Biological Sciences, many bacterial strains contain prophages. These prophages, she says, may provide defense systems that would make therapeutic uses of phages more challenging. In order to eradicate a pathogen, phages may need to overcome an already-in-residence prophage's defense systems.

Ware and her team (former PhD student Catherine Mageeney, current PhD student Hamidu Mohammed and former undergraduate student Netta Cudkevich), collaborating with former Lehigh Chemical and Biomolecular Engineering and Bioengineering faculty member Javier Buceta and his team (former postdoctoral associate Marta Dies, recent PhD students Samira Anbari and Yanyan Chen), recently conducted a study that focused on a phage called Butters (discovered by Lena Ma in Lehigh's SEA-PHAGES Program in 2012) that attacks a bacterial strain related to mycobacteria that cause tuberculosis or other human infections.

The group uncovered a two-component system of Butters prophage genes that encode proteins that "collaborate" to block entry and subsequent infection of some phages, but not others. While the Butters prophage cannot protect the bacterial cell against all phage attacks, they discovered that more than one defense system is present in the Butters prophage defense repertoire. These weapons, they discovered, are specific for different types of phages. These findings were published in an article earlier this month in mSystems, a journal of the American Society for Microbiology.

"Previous findings by several members of our research team working with other collaborators showed that prophages express genes that defend their bacterial host from infection by some specific groups of phages. For Butters, no genes involved in defense against specific phages had been previously identified," says Ware. "With our experimental approach, we expected to identify genes involved in defense against infection by several phages, but were not expecting to uncover interactions between the two proteins that affected how one of the proteins functions in defense."

The Ware/Buceta team used a multidisciplinary approach to identify the genes and interactions. They utilized bioinformatics tools to predict structural features of proteins encoded by genes expressed by the Butters prophage and to probe databases for the presence of Butters genes within known bacterial strains. Molecular biology techniques were used to engineer mycobacterial strains to express phage genes from the prophage. Microbiology experiments included immunity plating efficiency assays for each engineered bacterial strain to determine if the gene in question would protect the engineered bacterial strain from infection by a particular phage type.

This strategy, says Ware, allowed identification of specific genes as part of the defense mechanism against specific viral attack.

They also conducted microscopy experiments for live-cell imaging to visualize the cellular location of phage proteins within engineered bacterial cells and to show a functional interaction between the phage proteins in question. Biochemical experiments determined that the phage proteins likely interact physically as part of the defense mechanism.

"Collectively, these approaches provided data that allowed the team to construct a model for how the Butters prophage two-component system may function in defense against specific viral attack," says Ware.

Adds Ware: "The diversity of defense systems that exists demonstrates that efforts to establish generic sets of phage cocktails for phage therapy to kill pathogenic bacteria will likely be more challenging."

In addition to advancing phage therapy development, the team's discovery may also be important for engineering phage-resistant bacteria that could be used in the food industry and in some biotechnology applications.

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How do viruses choose whether to become nasty or not?

Bacteria-targeting viruses improve their decision making by co-opting the defense systems built against them

TEL-AVIV UNIVERSITY

 

IMAGE: 

LEFT TO RIGHT: PROF. AVIGDOR ELDAR & POLINA GULER.

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CREDIT: TEL AVIV UNIVERSITY

Researchers from the Shmunis School of Biomedicine and Cancer Research at Tel Aviv University have deciphered a novel complex decision-making process that helps viruses choose to turn nasty or stay friendly to their bacterial host. In a new paper, they describe how viruses co-opt a bacterial immune system, intended to combat viruses like themselves, in this decision-making process.

 

The study was led by Polina Guler, a PhD student in Prof. Avigdor Eldar's lab, in addition to other lab members, at the Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences. The paper was published in Nature Microbiology.

 

Bacteriophages, also known as phages, are types of viruses that infect bacteria and use the infected bacteria to replicate and spread. Even though the word 'bacteriophage,' meaning 'bacteria devouring' in ancient Greek, suggests destruction, many phages can adopt a "sleeping" mode, in which the virus incorporates itself into the bacterial genome. In fact, in this mode of action, the virus can even have a symbiotic relationship with the bacteria, and its genes can help its host prosper.

 

In general, Eldar explains that phages usually prefer to stay in the “sleeping”, dormant mode, in which the bacteria "cares" for their needs and helps them safely replicate. Previous research published by the Eldar lab has shown that the phages' decision-making uses two kinds of information to decide whether to stay dormant or turn violent: the "health status" of their host and signals from outside indicating the presence of other phages around.

 

"A phage can't infect a cell already occupied by another phage. If the phage identifies that its host is compromised but also receives signals indicating the presence of other phages in the area, it opts to remain with its current host, hoping for recovery. If there is no outside signal, the phage 'understands' that there might be room for it in another host nearby and it’ll turn violent, replicate quickly, kill the host, and move on to the next target," Eldar explains.

 

The new study deciphers the mechanism that enables the virus to make these decisions. "We discovered that in this process the phage actually uses a system that the bacteria developed to kill phages," says Guler. If it does not sense a signal from other phages—indicating that it has a good chance of finding new hosts—the phage activates a mechanism that disables the defense system. "The phage switches to its violent mode, and with the defense system neutralized, it is able to replicate and kill its host," describes Guler. "If the phage senses high concentrations of the signal, instead of disabling the defense system, it utilizes its defense activity in order to turn on its dormant mode."

 

"The research revealed a new level of sophistication in this arms race between bacteria and viruses," adds Eldar. Most bacterial defense systems against phages were studied in the context of viruses that are always violent. Far less is known about the mechanisms of attacks and interaction with viruses that have a dormant mode. "The bacteria also have an interest in keeping the virus in the dormant mode, first and foremost to prevent their own death, and also because the genes of the dormant phage might even contribute to bacterial functions," says Eldar.

 

“This finding is important for several reasons. One reason is that some bacteria, such as those causing the cholera disease in humans, become more violent if they carry dormant phages inside them - the main toxins that harm us are actually encoded by the phage genome," explains Eldar. “Another reason is that phages can potentially serve as replacements to antibiotics against pathogenic bacteria. Finally, phage research may lead to better understanding of viruses in general and many human-infecting viruses can also alternate between dormant and violent modes.”

 

Link to the article:

https://www.nature.com/articles/s41564-023-01551-3

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JOURNAL

Nature Microbiology

DOI

10.1038/s41564-023-01551-3 

Phages: Bacterial eaters from Georgia to fight antibiotic resistance

What are we to do when antibiotics are no longer effective? Patients from all over the world come to Georgia to be treated with bacteriophages. In the meantime, phage therapy is also available in Belgium.


Tanja Diederen lives near Maastricht in the Netherlands. She has been suffering from Hidradenitis suppurativa for 30 years. Its a chronic skin disease in which the hair roots are inflamed under pain — often around the armpits and on the chest.

€3,900 for treatment in Georgia

In August 2019, the now 50-year-old made a radical decision: she discontinued the antibiotics, which were becoming less and less effective. And she traveled to Georgia for two weeks to undergo treatment with bacteriophages (or phages for short).

Read more: Big Pharma nixes new drugs despite impending 'antibiotic apocalypse'

Radical decision: treatment with bacteriophages has helped Tanja Diederen

Such phage therapy is not yet approved in most Western European countries. She paid 3,900 euros out of her own pocket in the hope that the unconventional therapy would help her.

Bacteriophages are viruses that fight against the proliferation of their host bacteria. Therapy with bacteriophages involves the oral administration of a single, isolated type of phage. They attach themselves to their bacterial counterparts in the patient's body in order to survive.

Read more: Drug-filled rivers aiding resistance to antibiotics

Healing without antibiotics

The phages reverse the polarity of the bacterial cell in such a way that it produces further phages, filling up with more and more phages and finally bursts. Then, the released phages attach themselves to other bacteria until all of the bacteria has been destroyed.

Journey into the unknown

"It tastes a bit like mushrooms," Tanja Diederen remarked as she took her morning phage dose. "When I went to Georgia, I was at first very nervous and excited, but above all disappointed about the treatment here in Holland."

After antibiotics stopped working for her, her doctor suggested that she take biopharmaceuticals, i.e. genetically engineered drugs. He had never heard of bacteriophages.

Instead, Diederen decided to look for treatment options with bacteriophages on her own, which she had heard about in a television program. 

Read more: Superbugs kill 33,000 in Europe each year, says study

A phage model — phages are viruses, that multiply in bacteria and then destroy them

The doctor never heard of phages

She came across the Georgi-Eliava Institute in Georgia, which has been researching bacteriophages since 1923 — just a few years after their discovery. Georgia has since developed into the global center of phage therapy.

During the Cold War, antibiotics were difficult to get there or anywhere in the Soviet Union. Treatment with phages was the best way to cure infectious diseases. Today, the Eliava Institute has one of the largest therapeutic collections of bacteriophages in the world.

Tanja Diederen stayed in treatment for two weeks, after which she traveled back to the Netherlands with a large suitcase full of phage tins. Since she began taking two different phages a day and applying a cream, she feels better.

She has more energy again and the small inflammations on her chest and armpits have decreased. The large inflammations come and go, but not as severe as before.

"It doesn't feel illegal to me"

Every three months Diederen travels to Belgium — 15 kilometers away — to pick up a new ration of bacteriophages sent from Georgia for 500 euros. Her health insurance doesn't pay for this. Belgium is the only Western European country where phages are allowed. In the Netherlands, as in all other countries, they can only be used in individual cases to save lives or relieve severe pain.

Read more: Chicken meat rife with antibiotic-resistant superbugs

Communicating with the Georgian doctors was difficult for Tanja Diederen. She needed a translator.

Her physician is solely responsible for the application.

"It doesn't feel illegal to me," said Diederen. "I am one hundred percent sure that this medicine will help many people."

Like antibiotics, bacteriophages can also lead to bacterial resistance. Their big advantage, however, is that they are always one step ahead of the bacteria and can overcome the resistance. In addition, they are always directed against a specific type of bacteria and thus leave useful bacteria undamaged, like in the intestine, for example.

Before phage treatment, it is always necessary to determine which bacteria actually trigger the disease. The phages are then produced individually for each patient — often in Georgia.

Bacteriophages permitted in Belgium

Such an individual medication does not meet the applicable regulations for medicinal products in any Western European country. It would take too much effort to have each individual phage formulation approved by the authorities.

Read more: 90 years after penicillin: Artilysin could replace antibiotics

Professor Jean-Paul Pirnay from the Queen-Astrid Military 
Hospital in Brussels works with bacteriophages

Not so in Belgium. Since last year, this process can be legally circumvented by the Scientific Health Institute, in cooperation with doctors, patients, manufacturers, pharmacists and the Belgian Federal Office for Medicinal Products, issuing a certificate for the required phage ingredients. Pharmacists will then be able to use them for the manufacture of bacteriophages, subject to certain guidelines.

"We have used the existing legal framework to insert the bacteriophages," said Dr Jean-Paul Pirnay, who works at the Queen Astrid Military Hospital in Brussels on bacteriophages.

Around 30 patients have already been treated there. Currently, the military hospital is the only place in Belgium where bacteriophages are produced.

Useful supplement to antibiotics

"We need pharmaceutical companies to make the phage," says Pirnay. "A hospital can't produce all phages for a growing number of patients."

But industrial production of phages would require a clearer legal framework, and research is not yet ready.

"I believe that phages will not replace antibiotics," he said. "Both will be used together to make antibiotics more effective."

Tanja Diederen wants to continue her treatment in Brussels in the future. Communication with the Georgian doctors was difficult for her, she always needed a translator.

"I really hope that phages will soon be allowed in Europe," she said. "Going to Georgia is quite difficult and expensive."

Germany and the Netherlands are currently conducting pilot studies to see whether an individual prescription of bacteriophages would be possible. France has already imported Belgian phages and agreed to their use.

Read more: Beware of germs in hand dryers

BACTERIA, VIRUSES, MOLD: LIFE-THREATENING YET INDISPENSABLE

Ewww!
Just scrape the mold off, right? Wrong. A moldy old sandwich like this one is anything but harmless. While there are some harmless kinds of mold - like on Camembert cheese - many molds are toxic. Furthermore, mycelium spores can trigger allergies. Through contact with highly toxic types of mold, humans with weakened immune defenses could even die as a result of an extended exposure.

BACTERIA, VIRUSES, MOLD: LIFE-THREATENING YET INDISPENSABLE

Also viruses can contaminate food
Norovirus or stomach flu is transmitted person-to-person through traces of vomit or feces. Just 100 tiny norovirus particles are enough to infect someone. The virus can easily pass into the food chain via infected drinking water.


BACTERIA, VIRUSES, MOLD: LIFE-THREATENING YET INDISPENSABLE

Mold as a biocatalyst
Mold can also be useful: Fungi is able to break down carbon hydrates, fats and proteins - more efficiently than any other organism. Industry makes use of a genetically modified Aspergillus niger fungus, which produces enzymes that can be used in food processing and production of detergents - like a living factory.

BACTERIA, VIRUSES, MOLD: LIFE-THREATENING YET INDISPENSABLE

Salami tactics
"Botulus" is Latin for "sausage." If mistakes are made in the production of sausage, or if meat or vegetables get contaminated during canning, this can cause botulism. The bacteria Clostridium botulinum causes this life-threatening poisoning.

Fresh vegetables not always healthy 

Fenugreek sprouts were a favorite among Germans trying to eat healthy - until 2011. That year, seeds contaminated with the bacteria Escherichia coli (EHEC) caused an outbreak that killed 53 people - hundreds more were sickened. EHEC produces a toxin that destroys intestinal wall cells, and later attacks brain and kidney cells. Cooking raw vegetables and meat kills the harmful bacteria.                      

BACTERIA, VIRUSES, MOLD: LIFE-THREATENING YET INDISPENSABLE
A useful relative
But not all varieties of E. coli are dangerous. Inside the human large intestine, the bacteria are usually responsible for producing vitamin K - important for the development of bones and cells, and for blood coagulation. In biotechnology, the bacteria play a role in producing insulin and growth hormones. They can even be used for turning microalgae into alcohol-based biofuel.

BACTERIA, VIRUSES, MOLD: LIFE-THREATENING YET INDISPENSABLE

Bacteria preserves foods
Thousands of years ago, humans learned to use lactic acid bacteria - for the production of yoghurt, kefir, sourdough bread and cheese. Raw milk warmed to 20 degrees Celsius is heaven for bacteria: Within 10 hours, the milk will go sour. Milk fermented with the help of bacteria, however, can stay edible for much longer.



BACTERIA, VIRUSES, MOLD: LIFE-THREATENING YET INDISPENSABLE
Too much of a good thing

One of the many varieties of lactic acid bacteria are streptococci, which play a role in producing sauerkraut and fermented milk products. Although streptococci are everywhere - on humans, animals and plants - some of them are unhealthy. Some strains of strep can trigger tooth decay or sepsis, commonly known as blood poisoning.


BACTERIA, VIRUSES, MOLD: LIFE-THREATENING YET INDISPENSABLE
Dangerous diarrhea
Rod-shaped bacteria like Campylobacter and Salmonellae cause illness and death the world over. Undercooked beef, pork or chicken containing Campylobacter is a common cause of diarrhea wordwide. Typhus is the most dangerous form of salmonellae, triggering high fever, weak heartbeat and constipation. Every year, about 32 million people are si BACTERIA, VIRUSES, MOLD: LIFE-THREATENING YET INDISPENSABLE

Dangerous diarrhea
Rod-shaped bacteria like Campylobacter and Salmonellae cause illness and death the world over. Undercooked beef, pork or chicken containing Campylobacter is a common cause of diarrhea wordwide. Typhus is the most dangerous form of salmonellae, triggering high fever, weak heartbeat and constipation. Every year, about 32 million people are sickened from typhus - mainly by drinking impure water.

WWW LINKS

Wikipedia: Bacteriophages

Georgi Eliava Institute, Georgia

Research Gate: Pirnay Lab

AUDIOS AND VIDEOS ON THE TOPIC

HEALING WITHOUT ANTIBIOTICS   

cleaned from typhus - mainly by drinking impure water.

WWW LINKS

Wikipedia: Bacteriophages

Georgi Eliava Institute, Georgia

Research Gate: Pirnay Lab

AUDIOS AND VIDEOS ON THE TOPIC

Healing without antibiotics   

Author: Fabian Schmidt
SEE 
 https://plawiuk.blogspot.com/search?q=PHAGES
 https://plawiuk.blogspot.com/search?q=BACTERIOPHAGE
https://plawiuk.blogspot.com/search?q=PHAGE
 https://plawiuk.blogspot.com/search?q=BIOPHAGES

Author: Fabian Schmidt

BACTERIA, VIRUSES, MOLD: LIFE-THREATENING YET INDISPENSIBLE
Bacteria preserves foods

Thousands of years ago, humans learned to use lactic acid bacteria - for the production of yoghurt, kefir, sourdough bread and cheese. Raw milk warmed to 20 degrees Celsius is heaven for bacteria: Within 10 hours, the milk will go sour. Milk fermented with the help of bacteria, however, can stay edible for much longer.