Do dirty viruses make you sicker?

Recent paper we contributed to looked at the role of defective viral genomes in the disease after influenza virus infection.

I think we can all safely agree that the immune system is complicated; that viruses are complicated and when you combine the two the overall outcome is more complicated than the sum of its parts. In the current study (Levels of Influenza A Virus Defective Viral Genomes Determine Pathogenesis in the BALB/c Mouse Model) led by Becky Penn in Wendy Barclay’s group at Imperial College London, the question was what happens when the infectious virus (in this study influenza) contains more (or less) junk.

Viruses contain genetic information wrapped up in a protein coat. For a more detailed overview of what viruses are – can I recommend my book Infectious (out now in paperback). The immune system recognises viruses through a number of different ways, but one of them is through recognising the viral genetic material. In the case of influenza this is somewhat more simple because the genetic material is different to human genetic material. Humans pass their genes between different generations using DNA, but influenza uses a related molecule called RNA. Human cells also use RNA, but for different purposes – mostly for transmitting genetic information within the cell. The viral RNA therefore is a clear danger sign to cells that there is an infection. Viruses have evolved to hide their RNA from the immune system. They wrap it around proteins like thread wrapped around a cotton reel. This means the immune system can no longer see the RNA and reduces the response to it.

However, the amount of RNA is not constant. Sometimes individual virus particles fail to hide their RNA, which makes the immune response to them stronger. One factor that affects the packaging of the RNA is how the viruses grow. Becky manipulated the way that she grew her influenza virus, with some of the stocks having much more of these badly packaged viruses and some having neatly packaged genetic material. The theory was that the badly packaged viruses was, because they are more dirty trigger the immune response, what was unknown was how this would effect the outcome. There were 2 possibilities:

  1. The immune system would be so fast at seeing the virus, it would kill it before it ever took hold.
  2. The immune system would go into overdrive.

Surprisingly, the results were a bit of both. The dirty viruses (also called High DVG because they have more defective viral genomes) were indeed detected quicker by the immune system. This led to the release of signalling molecules called interferon. Interferons trigger an anti-viral state, shutting down the growth of virus within the cells.

The cleaner stocks performed very differently. They were initially able to escape the immune system and set up an infection in the lungs. This infection then, paradoxically, led to the production of the dirty viruses in the lungs of the infected animals. This production in the lungs led to a cycle of inflammation, basically putting fuel on the fire and increasing the severity of disease. This tells us that disease after viral infection is driven by a combination of factors – the damage caused by the virus itself and the immune response to the damage. On a more niche note, it tells us that the quality of experimental virus used is really important in shaping the outcome of the study. Which is one of the almost infinitely complicated variables in doing biological studies with 2 live agents (let’s not even begin talking about time of day, chronobiology and the impact that has!

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