Molecular Biology of Innate Immunity

In some cases, the same receptors are activated by one’s own molecules, in the absence of infection, leading to sterile inflammation. It is unclear which self-derived molecules activate the innate immune system during sterile inflammation and via which pathways. A sterile inflammatory response is important in autoinflammatory conditions and autoimmune diseases. It is also a hallmark of cancer and can impact on immune responses against a tumor.

By studying the molecular mechanisms that underly innate immune activation, we aim to identify new targets for therapeutic intervention in autoinflammatory conditions and to inspire strategies to promote immunosurveillance in cancer.

​Innate immunity

Innate immunity is the first line of defense against infection with a pathogen. In the case of a viral infection, virally-derived nucleic acids are detected in the cytosol of infected cells by DNA sensors and RNA sensors (known as RIG-I like receptors). Activation of these receptors triggers the production and secretion of type I interferons by many cell types. Interferons activate the interferon receptor (IFNAR) and this induces an antiviral state and the expression of hundreds of interferon-stimulated genes (ISGs), which restrict viral replication in many ways.

Nucleic acids, however, are integral components of our own cells and in some cases our own DNA and RNA molecules accidentally trigger the nucleic acid sensing machinery. This leads to a type I interferon response in the absence of an infection, i.e. sterile inflammation. This is seen, for example, in patients who suffer from type I interferonopathies, a group of severe diseases caused by single gene defects that lead to chronic and excessive interferon production. Such patients would benefit from treatments that block interferon production.

Type I interferons

Conversely, type I interferon production by tumor cells or tumor-infiltrating immune cells can improve disease outcome. Type I interferons can contribute to immune control of cancer by recruiting effector cells and by promoting antigen-cross presentation by dendritic cells. An intra-tumoral interferon signature often correlates with a better prognosis and a better response to different types of therapies. However, interferon production in tumors is often suboptimal. Therefore, strategies to boost intra-tumoral interferon responses hold great potential to improve cancer therapy.

How type I interferons are induced in these different disease contexts is largely unknown and the focus of our research. What type of endogenous RNA molecules activate RNA sensors? What mechanisms do cells have in place to prevent this? We are using novel methods, such as iCLIP (individual-nucleotide UV crosslinking and immunoprecipitation) and CRISPR/Cas9, to understand the molecular basis of self/non-self recognition by the nucleic acid sensors of the innate immune system. The goal of our research is identify novel strategies to steer sterile inflammatory responses into a certain direction and to use it to our own advantage.