Research Interests

The Frickel lab studies interferon gamma-driven human host responses to infection and inflammation. We specifically focus on pathways driven by host guanylate binding proteins (GBPs) and ubiquitin. The pathogens we are most interested in are Toxoplasma gondii and Salmonella typhimurium. Our lab has a strong interest in automated artificial-intelligence-driven image analysis.

Host defence to Toxoplasma gondii

The protozoan parasite Toxoplasma gondii infects a broad range of hosts, with a seroprevalence in man of about 30 per cent. It is unclear how Toxoplasma maintains the intricate balance between survival and host defense.

IFNγ, the main cytokine responsible for its control, activates cells to restrict intracellular parasite replication or to kill intracellular Toxoplasma. The outcome of an infection with Toxoplasma is determined not only by the host’s immune status, but also by the genotype of the infecting strain. The major cause of Toxoplasma pathogenesis results from parasite burden, concurrent with an over-stimulation of the immune system in the form of high levels of T helper cell type 1 cytokines, increased apoptosis and organ damage.

Our long-term goal is to identify IFNγ-driven novel pathways of host resistance to Toxoplasma in human cells. We are studying how the parasitophorous vacuole (PV) is remodeled within host cells to limit parasite replication. Additionally, we are interested in IFNγ-dependent immune defence mechanisms that in general can limit Toxoplasma viability. The pathways we study often also impact bacterial or other eukaryotic pathogens as well as Toxoplasma. Therefore, the Frickel lab strives to uncover human IFNγ-dependent host defence pathways of broad relevance to eukaryotic and bacterial pathogens.

Cellular immune pathways regulated by guanylate binding proteins (GBPs)

Human GBPs are a family of seven large (ca 65kDa) GTPases whose expression is upregulated by IFNg. Some GBPs can undergo C-terminal lipidation and traffic to microbial compartments. There, they drive access of microbial ligands to cytosolic sensors and/or directly assist in caspase activation leading to host cell death. We discovered that human GBP1 promotes the detection of Gram-negative lipopolysaccharide (LPS) and Toxoplasma DNA.

While direct targeting of pathogens by GBPs is recognised as a hallmark for their host defense function, it remains to be investigated how GBPs regulate protozoan and bacteria pathogen control distal from the infection. For example, we have described that in human epithelial cells, GBP1 can control Toxoplasma replication without localising to the parasite. The mechanism of this phenomenon is unclear.

We are defining the broader function of GBPs during infection and inflammation. Our goal is to further understand how this protein family controls cell intrinsic immunity in diverse human cells and in response to different insults.

Automated artificial-intelligence-driven image analysis

We have a strong interest in automated quantification of host-pathogen image experiments, combining classical image segmentation with artificial intelligence algorithms to substitute for biased manual assessment by the user. To this end we have created an adaptable workflow, capable of processing large quantities of fluorescent image data. We can now analyse and assess infection parameters on a single cell and single pathogen level amounting to the quantification of thousands of infection events.

HRMAn enables you to automatically analyse parameters of host-pathogen interaction derived from immunofluorescent experiments. HRMAn is a custom-built open-source analysis solution based in KNIME. HRMAn uses artificial intelligence to assess host protein recruitment to pathogens.