Scientists have discovered a crucial part of the process by which one of the world's most common and dangerous early childhood infections, respiratory syncytial virus, causes disease.
By analysing samples taken from infected infants and data from laboratory-mouse experiments, scientists at the University of Texas Medical Branch at Galveston determined that RSV interferes with airway cells' ability to produce enzymes that keep highly damaging molecules known as reactive oxygen species under control.
The virus does this by preventing the activation of a single protein needed for the expression of a variety of detoxifying enzymes.
Reactive oxygen species then accumulate; causing cell-killing oxidative stress and inflammation in both infected and uninfected airway cells - a major factor in the damage done by RSV infection.
The discovery could lead to new therapies for RSV, which was estimated to have caused at least 3.4 million hospitalisations and 199,000 deaths among children under five worldwide in 2005.
"The role of oxidative stress has been studied in everything from aging to asthma, but this is really the first study to implicate it in lung inflammation associated with viral infections," said Antonella Casola, an associate professor at UTMB Health and lead author of the study.
The researchers followed up earlier studies in human cell cultures with experiments that showed a substantial reduction in the expression and activation of antioxidant enzymes in the lungs of RSV-infected mice.
Further investigations revealed that mice infected by RSV had much lower levels of a protein called Nrf2 - a 'transcription factor' needed to prompt the production of enzymes that clean up reactive oxygen species.
"What was really striking is that Nrf2 is a kind of master switch controlling the machinery of these antioxidant enzymes, and it appears the virus blocks its activity," said co-author Roberto Garofalo.
"This is interesting because genetic factors have been shown to be associated with other airway diseases, and the obvious question now is do the children who develop the most severe disease in response to RSV also have an Nrf2 gene that favours a low level of expression of these antioxidant enzymes? Are we seeing a combination of two hits, one from the virus and one from genetics?" he said.
The apparent involvement of Nrf2 also opens an intriguing therapeutic possibility because compounds that induce cells to make more of the transcription factor are already in clinical trials as potential cancer therapies, said Garofalo.
As part of the investigation, the researchers measured biochemical markers of reactive oxygen species and levels of antioxidant enzymes in nasal samples from 30 infants with RSV infections.
The severity of the babies' disease ranged from relatively minor upper respiratory tract infections to full-blown lung disease requiring respiratory support from a ventilator.
"Our findings in patients were very consistent with what we saw in mice. We found a significant increase in markers of oxidative injury and a significant decrease in antioxidant enzyme expression corresponding to the severity of the disease," said Garofalo.
The study is published online March 4 in the American Journal of Respiratory and Critical Care Medicine.