MSGID: 1:317/3 6448a8eb   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Luring the virus into a trap    
    Heidelberg researchers describe mechanisms that could help prevent   
   infections with the influenza A and Ebola viruses    
      
     Date:   
         April 25, 2023   
     Source:   
         Heidelberg University   
     Summary:   
         Viruses like influenza A and Ebola invade human cells in a   
         number of steps. Research teams investigated the final stages   
         of viral penetration using electron tomography and computer   
         simulations. So-called fusion pores, through which the viral   
         genome is released into the host cell, play a central role in   
         these processes. If they can be prevented from forming, the virus   
         is also blocked. The Heidelberg scientists describe previously   
         unknown mechanisms, which might lead to new approaches to prevent   
         infections.   
      
      
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   FULL STORY   
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   Viruses like influenza A and Ebola invade human cells in a number of   
   steps. In an interdisciplinary approach, research teams from Heidelberg   
   University and Heidelberg University Hospital investigated the final   
   stages of viral penetration using electron tomography and computer   
   simulations. In the case of influenza A, they were able to determine   
   how the immune system fights off the virus using a small protein. For   
   Ebola viruses, they discovered that a specific protein structure must   
   be disassembled in order for an infection to take hold.   
      
   So-called fusion pores, through which the viral genome is released into   
   the host cell, play a central role in these processes. If they can   
   be prevented from forming, the virus is also blocked. The Heidelberg   
   scientists describe previously unknown mechanisms, which might lead to   
   new approaches to prevent infections.   
      
   Many viruses that infect humans are covered with a lipid membrane   
   that has glycoproteins that can dock with human cells. In viruses like   
   influenza A, which enter through the respiratory tract, these are the   
   spike proteins that mainly bind to epithelial cells in the nose and   
   lungs. In contrast, the highly infectious Ebola virus spreads through   
   direct contact with infected bodily fluids and can penetrate a broad   
   spectrum of cell types. After invading human cells, these viruses must   
   open a fusion pore between the virus membrane and the host membrane to   
   release their genome into the host cell and propagate.   
      
   To fight off the virus, the human immune system attempts to block the   
   formation of the fusion pore in a multi-stage process. Infected cells   
   sense the presence of the foreign genome and send a signal, in the   
   form of an interferon molecule, to as yet uninfected cells. This signal   
   triggers the uninfected cells to produce a small cellular protein called   
   interferon-induced transmembrane protein 3 (IFITM3). "This specialised   
   protein can effectively prevent viruses such as influenza A, SARS-CoV-2,   
   and Ebola from penetrating, but the underlying mechanisms were unknown,"   
   states virologist Dr Petr Chlanda, whose working group belongs to the   
   BioQuant Center of Heidelberg University and the Center for Integrative   
   Infectious Disease Research of Heidelberg University Hospital.   
      
   The researchers were now able to demonstrate that for influenza A viruses,   
   IFITM3 selectively sorts the lipids in the membrane locally. This prevents   
   the fusion pores from forming. "The viruses are literally captured in   
   a lipid trap.   
      
   Our research indicates that they are ultimately destroyed," explains   
   Dr Chlanda.   
      
   To analyse the structural details of viruses, Dr Chlanda and his team   
   took advantage of equipment from the Cryo-Electron Microscopy Network   
   at Ruperto Carola. In an interdisciplinary approach, the research   
   groups led by Prof. Dr Ulrich Schwarz of the BioQuant-Center and the   
   Institute for Theoretical Physics along with Prof. Dr Walter Nickel of   
   the Heidelberg University Biochemistry Center predicted this process with   
   the aid of computer simulations. In the context of antiviral therapy,   
   the researchers believe it is possible to develop lipid-sorting peptides   
   that insert themselves into the virus membrane, rendering the viruses   
   incapable of membrane fusion. "Such peptides could be used in a nasal   
   spray, for example," states Petr Chlanda.   
      
   In a second study, the Heidelberg researchers investigated the penetration   
   and fusion of the Ebola virus. The filamentous morphology of the virus is   
   determined by a flexible protein envelope known as the VP40 matrix protein   
   layer. "It has always puzzled us how this long virus could penetrate   
   the cell, fuse with the membrane, and release its genome," states   
   Dr Chlanda. Using their structural analysis of infected but inactive   
   cells provided by collaborators from the Friedrich Loeffler Institute in   
   Greifswald, the researchers discovered that this virus protein envelope   
   disassembles at a low pH, i.e. in an acidic environment. This step is   
   not least decisive for the formation of fusion pores, as further computer   
   simulations by Prof. Schwarz and Prof. Nickel showed.   
      
   During this process, the electrostatic interactions of the VP40 matrix   
   with the membrane are weakened, thereby reducing the energy barrier of   
   pore formation.   
      
   The results of the Heidelberg basic research suggest that a blockade of   
   the disassembly of this layer would be one way to maintain Ebola viruses   
   in a state that does not permit fusion pore formation. Similar to the   
   influenza A virus, the Ebola virus would then be lured into a trap from   
   which it could not escape.   
      
   The studies were part of the Collaborative Research Centre "Integrative   
   Analysis of Pathogen Replication and Spread" (CRC 1129) funded by the   
   German Research Foundation. The research results were published in both   
   "Cell Host & Microbe" as well as the EMBO Journal.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Viruses # Ebola # HIV_and_AIDS # Infectious_Diseases   
             o Plants_&_Animals   
                   # Virology # Microbes_and_More # Genetics #   
                   Molecular_Biology   
       * RELATED_TERMS   
             o Natural_killer_cell o Avian_flu o Virus o Gene_therapy o   
             H5N1 o Pandemic o T_cell o Antiviral_drug   
      
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   Story Source: Materials provided by Heidelberg_University. Note: Content   
   may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Sophie L Winter, Gonen Golani, Fabio Lolicato, Melina Vallbracht,   
         Keerthihan Thiyagarajah, Samy Sid Ahmed, Christian Lu"chtenborg,   
         Oliver T Fackler, Britta Bru"gger, Thomas Hoenen, Walter Nickel,   
         Ulrich S Schwarz, Petr Chlanda. The Ebola virus VP40 matrix layer   
         undergoes endosomal disassembly essential for membrane fusion. The   
         EMBO Journal, 2023; DOI: 10.15252/embj.2023113578   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/04/230425111207.htm   
      
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