Defective Viral Genomes Stimulate the Anti-RSV Immune Response

During replication in its human host RSV (respiratory syncytial virus) generates large numbers of defective genomes (DVGs), which have been found to stimulate the host's immune system to fight off the viral infection.

RSV is a major cause of severe respiratory illness in children and susceptible adults. Over the course of the infection the virus blocks the development of the innate antiviral immune response and can grow to high titers in the respiratory tract. Since the virus potently suppresses the immune system, it has been unclear as to how the immune system eventually overcomes the infection.

Investigators at the University of Pennsylvania (Philadelphia, USA; www.upenn.edu) have evaluated the likelihood that DVGs were linked to stimulation of the host's immune response.

Working with a mouse model, they showed that RSV DVGs stimulated the expression of antiviral genes, restricted viral replication, and prevented weight loss and lung inflammation. Mice infected with a modified strain of RSV that lacked DVGs experienced worse disease symptoms, including weight loss and lung tissue inflammation, and had higher levels of virus in their lungs than mice infected with RSV that had high levels of DVGs. Mice infected with the modified RSV also had lower expression levels of antiviral genes, such as interferon, than mice infected with the DVG-containing RSV.

In human cells, the antiviral response to RSV DVGs was dominated by the expression of IFN-gamma1 (interferon gamma1) over IFN-beta (interferon beta) and was driven by rapid intranuclear accumulation of the transcription factor IRF1 (Interferon regulatory factor 1). RSV DVGs were detected in respiratory secretions of hospitalized patients, and their amount positively correlated with the level of expression of antiviral genes in the samples.

"What we see is that DVGs are key in signaling the immune response to turn on," senior author Dr. Carolina Lopez, assistant professor of pathobiology at the University of Pennsylvania. "This is the first study that shows that DVGs can critically impact the outcome of an RSV infection and that they are present in infected humans. If you put virus containing a lot of these defective genomes into human lung samples, they all respond, but the difference was some patients' tissue could accumulate the DVGs faster than others and that correlated with outcome. That tells you that there are host factors that modulate this response to DVGs and that that could predict outcomes. So now we want to find out what those host factors are. We have very few tools to manage RSV infection, so we would obviously like to see if we can figure out a way to trigger an immune response and clear infection before any damage is done. That is the future."

The study was published in the September 3, 2015, online edition of the journal PLOS Pathogens.

Related Links:
University of Pennsylvania