MSGID: 1:317/3 6406bdf1   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Phage attacks shown in new light    
      
     Date:   
         March 6, 2023   
     Source:   
         University of Pittsburgh   
     Summary:   
         New methodology and tools provide an opportunity to watch in   
         unprecedented detail as a phage attacks a bacterium.   
      
      
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   FULL STORY   
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   As antibacterial resistance continues to render obsolete the use of some   
   antibiotics, some have turned to bacteria-killing viruses to treat acute   
   infections as well as some chronic illnesses.   
      
      
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   Graham Hatfull, the Eberly Family Professor of Biotechnology in the   
   Kenneth P.   
      
   Dietrich School of Arts and Sciences at Pitt, has pioneered the use of   
   these viruses -- bacteriophages, phages for short -- to treat infections   
   in chronic diseases such as cystic fibrosis. Although the importance of   
   resistance may have eluded the early discovers of antibiotics, Hatfull   
   is intent on understanding how bacteria become resistant to phages.   
      
   His lab has just discovered how a specific mutation in a bacterium results   
   in phage resistance. The results were published Feb. 23, in the journal   
   Nature Microbiology.   
      
   The new methodology and tools his team developed also gave them the   
   opportunity to watch in unprecedented detail as a phage attacks a   
   bacterium. As the use of phage therapy expands, these tools can help   
   others better understand how different mutations protect bacteria against   
   invasion by their phages.   
      
   For this study, the team started with Mycobacterium smegmatis, a harmless   
   relative of the bacteria responsible for tuberculosis, leprosy and other   
   hard- to-treat, chronic diseases. They then isolated a mutant form of the   
   bacterium that is resistant to infection by a phage called Fionnbharth.   
      
   To understand how the specific mutation in the lsr2 gene helps these   
   resistant bacteria fight off a phage, the team first needed to understand   
   how phages killed a bacteria without the relevant mutation.   
      
   Carlos Guerrero-Bustamante, a fourth-year graduate student in Hatfull's   
   lab, genetically engineered two special kinds of phages for this   
   study. Some produced red fluorescence when they entered a bacterial   
   cell. Others had segments of DNA that would stick to fluorescent molecules   
   so phage DNA would light up in an infected cell.   
      
   Following the fluorescent beacons, "We could see where the phage DNA   
   entered the cell," Guerrero-Bustamante said. The imaging methods they used   
   were designed by Charles Dulberger, a collaborator and co-first author   
   of the paper who was then at Harvard T.H. Chan School of Public Health.   
      
   "We saw for the first time how the phages take that first step of binding   
   to cells and injecting their DNA into the bacteria," said Hatfull, who   
   is also a Howard Hughes Medical Institute Professor. "Then we applied   
   those insights to ask, 'So, how's it different if we get rid of the   
   Lsr2 protein?'"  The link between Lsr2 and phage resistance has not been   
   previously known, but with their new methods and tools, the team clearly   
   saw the critical role it played.   
      
   Typically, Lsr2 helps bacteria replicate its own DNA. When a phage   
   attacks, however, the virus co-opts the protein, using it to replicate   
   phage DNA and overwhelm the bacteria. When the lsr2 gene is missing or   
   defective -- as in the phage-resistant Mycobacterium smegmatis -- the   
   bacteria doesn't make the protein and phages don't replicate enough to   
   take over the bacterial cell.   
      
   This was a surprise.   
      
   "We didn't know Lsr2 had anything to do with bacteriophages," Hatfull   
   said.   
      
   These new tools can be used to uncover all manner of surprises written   
   in the genes of phage-resistant bacteria. It may also help today's   
   researchers and tomorrow's clinicians to better understand and take   
   advantage of phages' abilities while avoiding the missteps that led to   
   antibiotic resistance.   
      
   "This paper focuses on just one bacterial protein," and its resistance   
   to just one phage, Hatfull said, but its implications are wide. "There   
   are lots of different phages and lots of other proteins."   
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                   # Bacteria # Microbes_and_More # Genetically_Modified   
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             o Dog_attack o Legionnaires'_disease o Visual_acuity o Tularemia   
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   ==========================================================================   
   Story Source: Materials provided by University_of_Pittsburgh. Original   
   written by Brandie Jefferson. Note: Content may be edited for style   
   and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Charles L. Dulberger, Carlos A. Guerrero-Bustamante, Sia^n V. Owen,   
      Sean   
         Wilson, Michael G. Wuo, Rebecca A. Garlena, Lexi A. Serpa, Daniel A.   
      
         Russell, Junhao Zhu, Ben J. Braunecker, Georgia R. Squyres,   
         Michael Baym, Laura L. Kiessling, Ethan C. Garner, Eric J. Rubin,   
         Graham F. Hatfull.   
      
         Mycobacterial nucleoid-associated protein Lsr2 is required for   
         productive mycobacteriophage infection. Nature Microbiology, 2023;   
         DOI: 10.1038/ s41564-023-01333-x   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/03/230306143446.htm   
      
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