Study demonstrated how phage can be engineered to produce bacteriocins and cell wall hydrolases as antimicrobial effector genes.
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Virus World
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Virus World provides a daily blog of the latest news in the Virology field and the COVID-19 pandemic. News on new antiviral drugs, vaccines, diagnostic tests, viral outbreaks, novel viruses and milestone discoveries are curated by expert virologists. Highlighted news include trending and most cited scientific articles in these fields with links to the original publications. Stay up-to-date with the most exciting discoveries in the virus world and the last therapies for COVID-19 without spending hours browsing news and scientific publications. Additional comments by experts on the topics are available in Linkedin (https://www.linkedin.com/in/juanlama/detail/recent-activity/)
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Juan Lama
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New Research Finds That Viruses May Have “Eyes and Ears” on UsThe newly-found, widespread ability of some viruses to monitor their environment could have implications for antiviral drug development. New research indicates that viruses are using information from their environment to “decide” when to sit tight inside their hosts and when to multiply and burst out, killing the host cell. The work has important implications for antiviral drug development. Led by the University of Maryland Baltimore County (UMBC), the study was recently published in Frontiers in Microbiology. A virus’s ability to sense its environment, including elements produced by its host, adds “another layer of complexity to the viral-host interaction,” says Ivan Erill. He is senior author on the new paper and professor of biological sciences at UMBC. Right now, viruses are taking advantage of that ability to their benefit. But he says that in the future, “we could exploit it to their detriment.”
Not a coincidence
The new study focused on bacteriophages, which are often referred to simply as “phages.” They are viruses that infect bacteria. In the study, the phages analyzed can only infect their hosts when the bacterial cells have special appendages, called pili and flagella, that help the bacteria move and mate. The bacteria produce a protein called CtrA that controls when they generate these appendages. The research revealed that many appendage-dependent phages have patterns in their DNA where the CtrA protein can attach, called binding sites. Erill says that a phage having a binding site for a protein produced by its host is unusual. Even more surprising, Erill and the paper’s first author Elia Mascolo, a Ph.D. student in Erill’s lab, discovered through detailed genomic analysis that these binding sites were not unique to a single phage, or even a single group of phages. Many different types of phages had CtrA binding sites—but they all required their hosts to have pili and/or flagella to infect them. They decided that it couldn’t be a coincidence. The ability to monitor CtrA levels “has been invented multiple times throughout evolution by different phages that infect different bacteria,” Erill says. When distantly related species exhibit a similar trait, it’s called convergent evolution—and it indicates that the trait is definitely useful. Timing is everything
Another wrinkle in the story: The first phage in which the scientists identified CtrA binding sites infects a particular group of bacteria called Caulobacterales. Caulobacterales are an especially well-studied group of bacteria, because they exist in two forms: a “swarmer” form that swims around freely, and a “stalked” form that attaches to a surface. The swarmers have pili/flagella, and the stalks do not. In these bacteria, CtrA also regulates the cell cycle, determining whether a cell will divide evenly into two more of the same cell type, or divide asymmetrically to produce one swarmer and one stalk cell. Since the phages can only infect swarmer cells, it’s in their best interest only to burst out of their host when there are many swarmer cells available to infect. Generally, Caulobacterales live in nutrient-poor environments, and they are very spread out. “But when they find a good pocket of microhabitat, they become stalked cells and proliferate,” Erill says, eventually producing large quantities of swarmer cells. So, “We hypothesize the phages are monitoring CtrA levels, which go up and down during the life cycle of the cells, to figure out when the swarmer cell is becoming a stalk cell and becoming a factory of swarmers,” Erill says, “and at that point, they burst the cell, because there are going to be many swarmers nearby to infect.” Listening in
Unfortunately, the method to prove this hypothesis is extremely difficult and labor-intensive, so that wasn’t part of this latest paper—although Erill and colleagues hope to tackle that question in the future. However, the research team sees no other plausible explanation for the proliferation of CtrA binding sites on so many different phages, all of which require pili/flagella to infect their hosts. Even more interesting, they note, are the implications for viruses that infect other organisms—even humans. “Everything that we know about phages, every single evolutionary strategy they have developed, has been shown to translate to viruses that infect plants and animals,” he says. “It’s almost a given. So if phages are listening in on their hosts, the viruses that affect humans are bound to be doing the same.” There are a few other documented examples of phages monitoring their environment in interesting ways, but none include so many different phages employing the same strategy against so many bacterial hosts. This new research is the “first broad scope demonstration that phages are listening in on what’s going on in the cell, in this case, in terms of cell development,” Erill says. But more examples are on the way, he predicts. Already, members of his lab have started looking for receptors for other bacterial regulatory molecules in phages, he says—and they’re finding them. New therapeutic avenues
The key takeaway from this research is that “the virus is using cellular intel to make decisions,” Erill says, “and if it’s happening in bacteria, it’s almost certainly happening in plants and animals, because if it’s an evolutionary strategy that makes sense, evolution will discover it and exploit it.” For example, an animal virus might want to know what kind of tissue it is in, or how robust the host’s immune response is to its infection in order to optimize its strategy for survival and replication. While it might be disturbing to think about all the information viruses could gather and possibly use to make us sicker, these discoveries also open up opportunities for new therapies. “If you are developing an antiviral drug, and you know the virus is listening in on a particular signal, then maybe you can fool the virus,” Erill says. That’s several steps away, however. For now, “We are just starting to realize how actively viruses have eyes on us—how they are monitoring what’s going on around them and making decisions based on that,” Erill says. “It’s fascinating.”
Research Cited Published in Frontiers in Microbiology (August 17, 2022):
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This Medical News article discusses the resurgence of phage therapy research for antibiotic-resistant infections. Three weeks after the patient was hospitalized in 2020 with sepsis stemming from diabetic foot ulcers, his medical team watched more than 1 billion viral particles drip into his veins. The unorthodox intravenous infusions of bacteria-infecting viruses—known as bacteriophages, or simply phages—were a Hail Mary. Typical antibiotics hadn’t worked, and even the heaviest-hitting cocktails in the antibacterial arsenal were proving feeble against the multidrug-resistant infection that was rapidly spreading through the man’s blood. About a month later, after nebulized phage therapy was added to the regimen, the patient was breathing on his own, off a ventilator for the first time in almost 2 months. A week after that, his cultures were clear of the carbapenem-resistant Acinetobacter baumannii respiratory infection. Since the beginning of the COVID-19 pandemic, the patient’s physician, Sohail Rao, MD, had braced for the novel coronavirus. Quickly, though, Rao, an immunologist and executive vice president of DHR Health in Edinburg, Texas, realized that SARS-CoV-2 wasn’t the only pathogen his staff had to worry about Patients in the hospital also were contracting bacterial infections that made them “morbidly sick,” Rao recalled in an interview with JAMA. Some of these infections became so drug-resistant that physicians had nothing left to treat them with. “We were using anything and everything that was available in our toolbox,” Rao said, but “we were losing the battle.” That’s when he came upon a case report from Israel, which led him to a microbiologist in the US Army, who connected him with an ex-Navy officer’s bacteriophage startup, which provided the century-old therapy that Rao administered to his patient....
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A team of biologists from the Wellcome Sanger Institute, the European Bioinformatics Institute and the Universidad de los Andes has identified 142,809 species of bacteriophages -- viruses that infect and replicate in bacteria -- living in the human gut. Using a DNA-sequencing method called metagenomics, Wellcome Sanger Institute’s Dr. Luis Camarillo-Guerrero and colleagues explored and catalogued the biodiversity of the viral species found in 28,060 public human gut metagenomes and 2,898 bacterial isolate genomes cultured from the human gut. “It’s important to remember that not all viruses are harmful, but represent an integral component of the gut ecosystem,” said co-author Dr. Alexandre Almeida, a postdoctoral researcher at the European Bioinformatics Institute and the Wellcome Sanger Institute. “For one thing, most of the viruses we found have DNA as their genetic material, which is different from the pathogens most people know, such as SARS-CoV-2 or Zika, which are RNA viruses.”
“Secondly, these samples came mainly from healthy individuals who didn’t share any specific diseases.” “It’s fascinating to see how many unknown species live in our gut, and to try and unravel the link between them and human health.” The researchers also identified a previously unknown clade of bacteriophages, named Gubaphage. This was found to be the second most prevalent virus clade in the human gut, after crAssphage, which was discovered in 2014. “An important aspect of our work was to ensure that the reconstructed viral genomes were of the highest quality,” Dr. Camarillo-Guerrero said. “A stringent quality control pipeline coupled with a machine learning approach enabled us to mitigate contamination and obtain highly complete viral genomes.” “High-quality viral genomes pave the way to better understand what role viruses play in our gut microbiome, including the discovery of new treatments such as antimicrobials from bacteriophage origin.” The team’s results form the basis of the Gut Phage Database, a highly curated database of phage genomes that will be an invaluable resource for those studying bacteriophages and the role they play on regulating the health of both our gut bacteria and ourselves. “Bacteriophage research is currently experiencing a renaissance,” said Dr. Trevor Lawley, a researcher at the Wellcome Sanger Institute. “This high-quality, large-scale catalogue of human gut viruses comes at the right time to serve as a blueprint to guide ecological and evolutionary analysis in future virome studies.”
Findings published in Cell (Feb. 18, 2021):
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