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How the genome of influenza viruses is organized in infected host cells

Sep 14, 2020 // Andreas Herrmann and colleagues have published their insights into the genesis of novel influenza viruses using new technology in Nature Communications

SARS-CoV-2 currently affects almost all areas of our lives worldwide. However, the flu caused by influenza viruses continues to be a danger to humans. Newly emerging influenza viruses could also trigger severe worldwide disease waves, as has happened in the past. A major cause of this potential is the organization of the viral genome.

While in SARS-CoV-2 the genetic information for the viral proteins is encoded on a single continuous segment, in influenza A viruses this data is distributed on eight different independent segments, the viral ribonucleoproteins (vRNPs). New combinations of segments of two different influenza A viruses can, under suitable conditions, lead to the creation of new viruses that are highly dangerous to humans.

In contrast to the parts of the closet, the segments of influenza A viruses can organize themselves into an intact genome (the assembled closet) via different routes. Ivan Haralampiev, former member of the IRI Graduate School, and Simon Prisner demonstrated this in their successfully completed doctoral theses. The work was done in the framework of the IRI-hosted Einstein Research Network „Single molecule RNA biology - dynamics and function of RNA from transcription to degradation“ funded by the Einstein Foundation.

Both theses were done in the research group 'Molecular Biophysics' headed by IRI Life Sciences founding spokesperson Andreas Herrmann at the Institute of Biology of the Humboldt University Berlin in close cooperation with the research group 'Influenza and other Viruses of the Respiratory Tract' of Thorsten Wolff at the Robert Koch Institute.

Segments of influenza A viruses can organize themselves to form a whole

An influenza A virus must deliver all eight segments into the host cell in order for new, intact viruses to form. Previous work has provided evidence of a mechanism that ensures that any virus that develops receives all eight segments. However, it has not yet been clarified whether this mechanism ensures the formation of a complete segment bundle by a defined, strict sequence when joining the segments or whether these segments can also be combined with each other in different ways.

Applied to the products of a well-known Scandinavian furniture store, the question arose whether the individual parts of a closet (of the viral genome) must be assembled according to a precise construction plan or whether these individual parts can be combined in different flexible sequences to form a whole.

Technology might become a game changer in strategies for fighting viruses

With a new technique and the support of other scientists in Germany and abroad, it was possible for the first time to visualize all eight segments in parallel in infected human host cells using fluorescence microscopy. This flexibility in the structure of the genome is an evolutionary advantage, as it favors the formation of new virus subtypes, which can then also cause pandemics.

When two different subtypes of the influenza virus infect the same host, typically pigs or ducks, and the segments of the two viruses mix, new 'functional' subtypes with a new combination of segments can be created. This would be like assembling a new functional closet from the parts of two different closets. An infection caused by such viruses can pose an insurmountable challenge to the human immune system.

The new technology used by the researchers could lead to new strategies for fighting viruses by preventing the correct segment bundling.

Left: Schematic representation of the genesis of influenza viruses in the host cell. After uptake of the virus into the cell (endocytosis), the eight different vRNP segments are released from the virus envelope. The segments are transported into the cell nucleus. Here the information encoded on the RNA of the vRNPs is read. After several steps, not only new viral proteins are formed, but also new vRNP segments in the cell nucleus. The segments are transported from the nucleus to the cell membrane. In this way, segment bundles consisting of the eight different segments are formed. The bundles are then incorporated into the assembling viruses. Subsequently, the viruses cut themselves off from the cell.

Right: Fluorescence microscopic detection of two of the eight different vRNP segments in infected human lung epithelial cells. The images show two cells (cell nucleus appears dark).

Haralampiev, I., Prisner, S., Nitzan, M., Schade, M., Jolmes, F., Schreiber, M., Loidolt-Krüger, M., Jongen, K., Chamiolo, J., Nilson, N., Winter, F., Friedman, N., Seitz, O., Wolff, T., Herrmann, A. (2020) Selective flexible packaging pathways of the segmented genome of Influenza A Virus. Nature Communications, doi: 10.1038/s41467-020-18108-1

Prof. Dr. Andreas Herrmann
Molekulare Biophysik, Institut für Biologie, IRI Life Sciences
Humboldt-Universität zu Berlin
Phone: +49 30 2093 8860