Transgenic Mice to Combat Influenza Pandemics
A team from the University of Freiburg in Germany have developed a transgenic mouse model which may be able to help identify novel influenza virus strains that put humans at risk. The work, published today in the Journal of Experimental Medicine, also provides greater insight into how influenza viruses make the jump from animals to humans.
Influenza A viruses have been responsible for a number of global health crises throughout history, including the Spanish flu pandemic that resulted in between 50 million and 100 million deaths from 1918-1919 and the current H1N1 pandemic that’s impacting both human and porcine populations. The virus has been known to pass from pigs, birds, and other animal species to human populations via a series of mutations that enable the virus to avoid the human immune system.
This new study is focused on an innate immune protein called MxA, which is one of the components an influenza virus needs to avoid to infect humans. In human cultured cell lines, MxA can protect the cells from avian influenza viruses but doesn’t block viruses of human origins.
The team want to investigate whether or not MxA could prevent cross-species infection in the same way in vivo. To do this, they engineered transgenic mice that expressed the human form of MxA instead of the mouse form, and examined their resistance to influenza viruses. They found that, as in the cell lines, the mice were resistant to avian flu strains, but remained susceptible to human-sourced viruses.
Further investigation found that MxA worked by binding to the nucleoprotein which encapsulates the genetic material of the virus. Mutations with this nucleoprotein have been linked to the effectiveness with which the virus can infect humans, which the team theorised may be linked to its ability to bind with MxA. To test their theory, the team engineered an avian influenza virus to express the mutations within the nucleoprotein and exposed the transgenic mouse model to it, resulting in the mice becoming infected.
The study was therefore able to conclude that MxA acted as a barrier to cross-species contamination of influenza A viruses, but that a few mutations in the nucleoprotein enabled the viruses to avoid it. The team believe that their mouse model has the potential to monitor the dangers of emerging viral strains by identifying those which can affect humans.
“Our MxA-transgenic mouse can readily distinguish between MxA-sensitive influenza virus strains and virus strains that can evade MxA restriction and, consequently, possess a high pandemic potential in humans,” said Peter Staeheli, Ph.D., team leader and Professor at the Institute of Virology, Medical Centre University of Freiburg. “Such analyses could complement current risk assessment strategies of emerging influenza viruses, including viral genome sequencing and screening for alterations in known viral virulence genes.”