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Influenza infection
It might start with a sneeze but the underlying infection can cause far worse.
Hundreds of thousands of people every year die from severe influenza virus infection.
Everything begins when the virus enters our airways.
Here, influenza viruses specifically attach to the surface of epithelial cells.
The viral membrane envelope contains the neuraminidase protein: NA
important for efficient release of newly produced viruses.
The M2 ion channel promotes viral structural changes during cellular entry.
And the influenza haemagglutinin protein HA, the key player for viral internalization
which facilitates viral binding to sialic acid decorated receptors and subsequently viral fusion.
Proteolytic cleavage by host enzymes is critical for the activation of the HA trimers.
Soluble or cell-bound host proteases cleave the precursor HA molecules into two parts: HA1 and HA2.
Influenza virus particles are internalized into early endosomes by clathrin-mediated endocytosis.
In late endosomes the pH drops, triggering the conformational change of the cleaved HA molecules.
HA1 opens up and allows HA2 to forms a triple alpha helix bundle which extends towards the endosomal membrane.
Once the fusion peptides are anchored in the endosomal membrane
the whole molecule can fold back allowing the fusion of the viral and endosomal membranes.
After fusion, the viral genome can be released into the cytosol.
The eight viral RNA segments make their way into the cell nucleus
and the production of new viruses begins.
Just hours after the initial infection, thousands of new viruses bud off the cell surface and infect neighboring cells.
To stop the influenza infection, Crucell researchers have discovered fully human monoclonal antibodies capable of neutralizing the virus.
These antibodies specifically bind to the HA and are internalized together with the virus.
When the pH drops in late endosomes,
the antibodies remain bound to a highly conserved epitope
located in the stem of the HA.
The antibodies now block the conformational change of HA,
thereby preventing viral fusion and infection.
The trapped virus degrades, leaving the cell unharmed.
Some of Crucell’s new antibodies can also prevent the initial cleavage of HA.
They bind to a highly conserved epitope close to the HA cleavage site
thereby preventing host proteases from activating the virus.
The uncleaved virus is not infectious
so cell and patient are safe.