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Walter Reed Hospital flu ward during the Spanish Flu epidemic of 1918-19, in Washington D.C.

Influenza in all its strains and mutations is a constant killer, adapting its methods to infect and circumvent the best attempts to predict what’s coming next season.

But pandemic flus – the contagions that rip across countries, and have killed millions – are a matter of biological chance. These deadliest of all strains arise when viruses from different species mix into one cell, and then create a mutant for which no one is prepared.

Predicting what strains may mix and match their genes to create the perilous hybrids may be possible at the genome level, according to a new study by scientists at Washington University in St. Louis, published in Nature Communications.

They took some historical and contemporary flu viruses, genetically matched them in an attempt to understand what makes most dangerous RNA match, they report.

“Influenza A viruses can reassort and generate novel and potential pandemic strains,” they write in the paper. “These RNA features may be required for all viruses as coordinating packaging elements, but additional regions act as strain or lineage-specific packing enhancers. Further, these strain or lineage-specific RNA features, required for genome packaging, may act as potential determinants of reassortment outcomes.”

The scientists began with Madin-Darby Canine Kidney cells, a line that is uniquely tailored to be a mammalian model for studying virus infections.

The cells were then infected with both contemporary strains of Influenza A – such as a strain of H1N1, and H7N3 and some other mutants – with historical viral samples. Those viruses of the past included a strain of H1N1 from Puerto Rico collected in 1934, another H1N1 from California sampled in 2009, and a variety of H7N3 taken from a bird in Delaware in 2006.

The mixing and matching of the DNA was then assessed by the PAR-CLIP method of looking at the binding sites, in conjunction with next-generation sequencing.

The flu genome is broken into eight parcels of RNA, they demonstrated. Those parcels are contorted into 3-D shapes of genetic information. When the mutations change the shape, it compromises the viral replication. But when a change slips in without changing the shape, it can mean a whole new flu.

Finally, mice were infected with the mutant strains to understand their virulence – and how efficiently they replicate.

The scientists said in a school statement that they were hoping a wider database of global flu strains, from pigs to humans to birds, would help modern medicine focus on the danger zones in preparation for the next big outbreak.

“We think that two strains need to have similar features in their genome to re-assort and make a new virus,” said Adrianus Boon, the senior author, of Washington University. “But if we know that the viruses from a certain species or a certain region just don’t have the right RNA features, then we can make surveilling them a lower priority.

“If we can focus our resources more effectively, we may be able to catch the next pandemic flu before it really gets going,” he added.

Last year, the CDC estimated that the H7N9 strain of bird flu in China was the most likely to cause the next pandemic. However, scientists and vaccine makers have determined that this year’s flu shot, made off predictions for just this season, has not been particularly effective.

 

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