Molecular mechanisms by which the large GTPase hGBP1 inhibits actin-based bacterial dissemination

• Applicant: Professorin Dr. Miriam Kutsch
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Immunology
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427472513

Several species of invasive bacteria including the human-adapted, enteric pathogen Shigella enter host cells via endocytosis or phagocytosis and subsequently escape from an intracellular vacuole into the host cell cytosol. Survival within the cytosolic milieu drove the evolution of specific niche adaptations. One adaptation commonly found amongst intracytosolic bacterial pathogens such as Shigella is the ability to hijack the host’s actin polymerization machinery in order to generate force for intracytosolic movement and the invasion of neighboring host cells. This actin-based motility enables Shigella to spread within the colonic epithelium while simultaneously avoiding extracellular immune mechanisms such as antimicrobial peptides or neutrophils. Host defense against Shigella is therefore critically dependent on immune defense programs executed by the infected cell itself. One such cell-autonomous defense program directed at Shigella is executed by the dynamin-related GTPase human guanylate-binding protein 1 (hGBP1). Two independent studies reported that hGBP1 binds to Shigella and blocks bacteria from utilizing the host actin polymerization machinery for intracytosolic motility and cell-to-cell spread. The mechanisms underlying this potent hGBP1-mediated defense program is currently unknown and represents a critical gap in knowledge. My proposal aims to define the molecular mechanisms (1) by which hGBP1 recognizes and binds to Shigella as well as (2) by which hGBP1 prevents actin-based motility of Shigella. The multidisciplinary research proposal builds on prior work I and co-workers conducted in my host lab. The proposal integrates my biochemical and biophysical expertise to break a new frontier in "the battle over actin" between a medically relevant pathogen and the human host.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Dr. Jörn Coers