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 ========================================================================== 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

========================================================================== Story Source: Materials provided by Heidelberg_University. Note: Content
may be edited for style and length.


========================================================================== 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/04/230425111207.htm

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