Influenza A Viruses / R. Dourmashkin. Wellcome Images

The mechanism by which the virus Influenza A replicates itself within human host cells has been identified by researchers from the Icahn School of Medicine at Mount Sinai. The study, published in Cell, was able to observe how the virus hijacked the host’s cellular machinery, the RNA exosome, to reproduce within the nucleus. The team also identified links between rare defects in the machinery brought about by a rare mutation and the neurodegeneracy observed in the same patients.

Influenza A is responsible for a number of health concerns, including a number of seasonal flu cases and the more serious outbreak of H1N1 that impacted human and porcine populations worldwide in 2009. Despite a large amount of research having been carried out, the mechanisms involved in viral replication inside host cells haven’t been well understood.

This research was aimed at changing this. Using both healthy cells and cells from patients with an RNA exosome mutation donated from six different medical centres, the team observed how Influenza A was able to hijack the machinery in order to perform reproduction. They found that viral ribogenesis and growth was suppressed in patients with the mutation.

“This study shows how we can discover genes linked to disease – in this case, neurodegeneration – by looking at the natural symbiosis between a host and a pathogen,” said Ivan Marazzi, Ph.D., senior investigator and Assistant Professor in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai.

In healthy cells, the RNA exosome is a protein complex responsible for degrading RNA as part of gene regulation. As the loss of the functional complex severely compromises viral activity, as well as causing neurodegeneration, the team concluded that the virus was specifically targeting essential proteins within the cells to ensure future proliferation.

Unlike most viruses, which replicate in the cytoplasm, Influenza A is an RNA virus that needs to enter the nucleus to reproduce. To start the replication process, the virus needs extra RNA. The researchers found that in order to obtain this RNA, the virus ‘stole’ RNA molecules from the machinery itself.

“Viruses have a very intelligent way of not messing too much with our own biology,” said Dr. Marazzi. “It makes use of our by-products, so rather than allowing the exosome to chew up and degrade excess RNA, it tags the exosome and steals the RNA it needs before it is destroyed.”

“Without an RNA exosome, a virus cannot grow, so the agreement between the virus and host is that it is okay for the virus to use some of the host RNA because the host has other ways to suppress the virus that is replicated,” said Alex Rialdi, M.P.H., lead author.

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