Multiple ways to fight an infection

Despite its importance in combating disease, the cell biology of the inflammasome remained unclear. However, the EU-funded INFLAFRAN (Cell biology of inflammasome activation in macrophages infected with Francisella) project has shed light on how it is activated and interacts with other inflammatory pathways as well as bacterial virulence factors. The work promises to have an impact on research into the innate immune system, fighting infections and inflammation pathways.

The INFLAFRAN team used Francisella tularensis, a pathogenic bacterium causing tularaemia. Its virulence is linked to its ability to replicate within the cytosol of a type of white blood cell, macrophages. The outcome of the infection depends on the balance between bacterial virulence factors and host immune responses. This includes the inflammasome and the pathways that clean up after degradation of cell components.

During previous research, scientists had shown that Francisella is detected by the macrophages through the AIM2 inflammasome. AIM2 then interacts with the inflammasome adaptor ASC leading to caspase-1 activation. Under INFLAFRAN research, they found that AIM2 and ASC can also trigger caspase-8 that will cause cell death or apoptosis. This is highly significant as host cell death is an important factor in fighting bacteria by preventing their replication.

In another strand of the research, one more link to fighting pathogens was discovered – interferon gamma. While validating how caspase-8 inactivation occurs in a mouse model, researchers also discovered that the cytokine can be generated in a caspase-1 independent manner.

Research results are significant as they show how robust the innate immune system is. There are several pathways to fight microbes that are constantly evolving mechanisms to avoid and counteract innate biochemical cascades. Despite closure of the project, work is still continuing on a Francisella virulence factor that inhibits Toll-like Receptor 2 signaling (another innate immune signaling pathway).

In the project period, papers have been published on membrane-damaging virulence factors and caspase-1. There is also a book chapter and several reviews aimed at doctors and the public.