Lung Cell Protein Triggers a Dangerous Immune Response

A protein in the cytoplasm of lung cells helps protect against viral infection, but following invasion by the influenza virus, the same protein stimulates the immune system to overact, which can lead to inflammation or pneumonia.

Individuals infected with influenza become ill not only because of the presence of virus but also because of the inflammatory immune response triggered by reaction to the virus.

The Z-DNA binding protein 1 (ZBP1, also known as DNA-dependent activator of IFN regulatory factors) gene encodes a Z-DNA binding protein. Z-DNA formation is a dynamic process, largely controlled by the amount of supercoiling. ZBP1 recognizes DNA in the cytoplasm as an antiviral mechanism. Viral life cycles often include steps where DNA is exposed in the cytoplasm. DNA is normally contained in the nucleus of a cell, and therefore cells use proteins like ZBP1 as an indicator of a viral infection. Once ZBP1 is activated, it increases the production of antiviral cytokines such as interferon-beta (INF-beta).

Investigators at St. Jude Children's Research Hospital (Memphis, TN, USA) initially demonstrated that ZBP1-mediated sensing of the influenza A virus (IAV) proteins NP and PB1 triggered cell death and inflammatory responses.

In order to further clarify the role of ZPB1 in flu infection, they used genetic engineering techniques to create a line of mice that lacked the ZBP1 gene.

The investigators reported in the August 12, 2016, online edition of the journal Science Immunology that mice lacking ZBP1 showed an increased viral load and delayed recovery. On the other hand, these mice had decreased inflammation and less epithelial damage than control animals.

"Our discovery was totally unexpected," said senior author Dr. Thirumala-Devi Kanneganti, an immunologist at St. Jude Children's Research Hospital. "We never thought we would actually identify this molecule to be important in influenza viral infection, because there is no DNA stage in the influenza life cycle. ZBP1 does an amazing job of killing off infected cells. But it would be very useful to modulate ZBP1 in later stages of the infection, when the uncontrolled inflammation causes damage."

"Since the pathology that we saw in the mice matches what is seen in humans, we will now explore translating these findings to humans," said Dr. Kanneganti. "If we can somehow modulate the activation of this pathway, that will help to decrease the exaggerated inflammatory response that causes mortality during influenza infection. We have shown that these molecules are important in viral infections, but now we want to test their role in other inflammatory conditions. ZBP1 is likely not dedicated to attacking only the influenza virus. Maybe it also plays other roles, and if we fully understand those roles, we can learn how to manipulate immune responses."

Related Links:
St. Jude Children's Research Hospital