Tackling immune response could be promising new direction for flu drugs

Severity of a viral infection is partly due to the virus and partly due to the immune system's response. Now a new study led by the University of Washington in Seattle suggests that turning down the immune response, rather than trying to tackle the virus, might be a better way to reduce severity of illness.

The researchers report their findings in the Journal of Virology, where they demonstrate such an approach might be effective in fighting infection by the H7N9 avian flu virus.

The researchers have identified six potential drugs as candidates to treat avian flu.

They describe how they investigated the response to H7N9 in mice and compared it to responses elicited by other serious flu viruses, as well as less severe ones.

The researchers looked for genes that are turned on by the highly virulent strain of avian flu, which could lead to new drug therapies .

Michael Katze, Professor of Microbiology at the University of Washington, says they discovered "viruses that cause severe illness, like H7N9 and the infamous 1918 virus, trigger gene expression signatures that are different from the signatures seen in milder infections."

"Importantly, we can exploit these signatures for antiviral drug discovery," he adds.

Dr. Juliet Morrison, who works in the Katze Lab as a Project Manager for Emerging Infectious Disease Studies, says they used a computational approach to find candidate drugs.

The logic they followed was to find drugs that did the opposite of what H7N9 does in cells. When the virus enters a host cell, it has the effect of switching on a pattern of genes. So they looked for drugs that triggered expression profiles that were the opposite to those switched on by the virus. They deduce these might dampen down the immune response.

So they searched databases containing gene expression profiles that different drugs produce in cultured human cells and found those that matched the opposite to the profile elicited by H7N9.

Six drugs that might turn down the immune response already FDA-approved

Dr. Morrison says six of the drugs are already approved by the Food and Drug Administration (FDA) and could potentially be repurposed to treat H7N9 influenza.

H7N9 first appeared in February 2013 and those who caught the virus became very ill, as did victims of the 1918 flu pandemic, the deadliest on record.

The researchers found these severe flu viruses elicited three particular gene reactions in their mouse hosts: the severity of reaction was linked to increased transcription of inflammatory cytokine genes, and reduced transcription of lipid metabolism and coagulation genes. In their paper they refer to this as a "three-pronged transcriptomic signature."

They suggest further investigation of this signature will lead to greater understanding of severe flu viruses and the responses they elicit and should help identify more drugs that might turn down those responses.

 Using a "molecular clock" they traced the pandemic virus back to an H1 virus that had been circulating among humans since around 1900 and then picked up genetic material from a bird flu virus just before 1918.