Heidelberg University and Heidelberg University Hospital have discovered previously unknown mechanisms in influenza A and Ebola viruses that may help generate new strategies against infection. For their work, published in Nature Communications, the researchers analyzed the last stages of viral penetration using electron tomography and computer simulations. They found that the interferon-induced transmembrane protein 3 (IFITM3) selectively sorts the lipids in the membrane locally, preventing the formation of fusion pores in influenza A viruses. In Ebola viruses, they discovered that the VP40 matrix protein layer disassembles at a low pH, reducing the energy barrier of pore formation.
Influenza A viruses enter the body through the respiratory tract, whereas the Ebola virus spreads through direct contact with infected bodily fluids. After invading human cells, both viruses must open a fusion pore between their own membrane and the host membrane to propagate their genome into the host cell.
The human immune system attempts to block the fusion pore’s formation in a multi-stage process, where infected cells send out a signal, or an interferon molecule, to uninfected cells, triggering them to produce IFITM3.
The team used equipment from the Cryo-Electron Microscopy Network at Ruperto Carola to analyze the structural details of these viruses. They took an interdisciplinary approach, using computer simulations and collaborating with researchers from other institutions. They predicted lipid-sorting peptides could be developed and inserted into the virus membrane, rendering those viruses incapable of membrane fusion.
Ultimately, the team found that IFITM3 selectively sorts the lipids in the membrane locally, preventing the formation of fusion pores in influenza A viruses. In Ebola viruses, the VP40 matrix protein layer disassembles at a low pH, reducing the energy barrier of pore formation. This discovery could help maintain Ebola viruses in a state that does not permit fusion pore formation.