Sensing pathogens
My group mainly focuses on how enteric bacterial pathogens are detected by human cells.
The pathogens we investigate are enteropathogenic E. coli (EPEC), Salmonella and Shigella. We collaborate with wonderful colleagues on various aspects of work in this theme, including Eva-Maria Frickel, Gad Frankel, and Abigail Clements.
We discovered the unconventional activation of caspase-4 in human macrophages infected with EPEC (Goddard et al). This requires the EPEC outer membrane protein (Intimin) and Tir (Translocated intimin receptor) which is injected into the host cell.
Enteric bacteria such as Salmonella Paratyphi A (Mylona 2021) and Shigella sonnei (Watson 2019) avoid detection by the caspase-4/11 pathway through modifications of the LPS layer.
Guanylate-binding proteins (GBPs) have been a longstanding interest of mine. These are large GTPases (~65 kDa) that are induced by interferons, especially IFN\(\gamma\). See Fisch 2019 and Fisch 2020.
GBP1 targets cytosolic Salmonella as well as Toxoplasma gondii vacuoles in IFN\(\gamma\)–stimulated human macrophages.
Detecting EPEC, Salmonella and Shigella infection of host cells
- EPEC activates caspase-4/11 inflammasome pathways, also called non-canonical inflammasome signalling, through Tir-intimin signalling and actin remodelling at sites of bacterial attachment. This drives rapid activation of caspase-4, leading to pyroptotic cell death.
Salmonella Paratyphi A evades caspase-4 by expressing long O antigen chains and Shigella sonnei does so because it expresses a group 4 capsule. Thus, these bacteria use similar strategies, however, through different cellular pathways that modify their surfaces.
Sensing pathogens via GBPs
GBP1 targets cytosolic Salmonella in human macrophages, and this requires its GTPase activity and ability to oligomerise.
