A New Approach to Influenza Therapy: Reducing the Serious Risks of Influenza by Targeting an Inflammatory Pathway

In a study by Padmini Pillai, MA, and colleagues, published in Science on April 22, 2016, the researchers reported the results of an investigation of the role of an immune signaling pathway that may have an important role in mediating the immune response to influenza A virus infection. The pathway, which is mediated by a protein known as, myxovirus resistance protein 1 (mx1), may help stimulate interferon-mediated immune response to influenza A virus in humans. In the course of investigating this pathway, the researchers identified a gene that controls the potential for life-threatening immune-mediated responses to influenza A virus infection.

This gene may be a target for future therapeutic modalities to control the serious life-threatening consequences of influenza A infection, including secondary bacterial infections and damage to lung tissue.

The researchers examined peripheral blood monocytes from young adults aged 20 to 30 years, and older adults aged 65 to 89 years. After infecting the peripheral blood monocytes with the influenza A virus, the researchers identified more robust interferon-mediated responses in younger adults than in older adults on measures of proinflammatory cytokines expression and secretion. These findings suggest that impaired signaling of interferon pathways in older adults may lead to poor immune response to influenza A virus infection.

To further examine the role of weak interferon responses in older adults, the researchers analyzed responses to influenza infection in 2 sets of mice: an older group of mice with the C57BL/6 mutation, and younger mice. Contrary to expectation, the older mice with the C57BL/6 mutation were not more susceptible to influenza A virus infection than younger mice, and in fact, showed improved resistance to influenza A infection.

The mutated older mice were different from the younger mice on the genetic level primarily in that they did not carry functional alleles of the mx1 gene. This gene is important in the interferon-mediated immune response to influenza A infection.

To examine how inactive mx1 affects innate immunity, the researchers inactivated 3 additional genes involved in the immune response to influenza A virus infection in mice lacking mx1: TLR7, CASP1/11, and MAVS.

Unexpectedly, the engineered mice with all 3 additional genes inactivated continued to be protected from influenza A virus infection. Upon further analysis, this effect was found to be primarily mediated by lack of the CASP1/11 gene. Specifically, mice with inactive CASP1/11, as well as TLR7 and MAVS, survived longer than mice with only inactive TLR7 and MAVS after exposure to 10,000 plaque-forming units of the 2009 pandemic influenza H1N1 strain. These improvements in survival occurred despite the fact that viral loads over time were similar in both groups.

These results indicate CASP1/11 as a new potential therapeutic target for the treatment of patients at risk for serious adverse consequences of influenza A virus infection. Rather than treating influenza A viruses directly, future therapeutics targeting CASP1/11 could allow the influenza A virus to run its course, while minimizing the immune-mediated pathogenic effects of the virus, which appear to be controlled by CASP1/11. These results suggest that this new therapeutic option could potentially reduce the most serious consequences of influenza infection without directly targeting the virus.