Breaking down barriers: how surfactant GBP1 disrupts bacterial membranes

• Applicant: Professorin Dr. Miriam Kutsch
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560457894

To detect invading microbial pathogens, the innate immune system employs a variety of extra- and intra-cellular immune sensors to recognize conserved microbial molecules such as the Gram-negative bacterial surface molecule lipopolysaccharide (LPS). LPS consists of an outward facing O-antigen polysaccharide, inner and outer core oligosaccharides, and a lipid A moiety which interacts with glycerophospholipids to form an asymmetric lipid bilayer, the outer membrane. Ionic and non-ionic interactions between LPS molecules contribute to transforming the bacterial envelope into an effective permeability barrier which protects pathogenic bacteria from antimicrobials. We recently identified the large GTPase human guanylate binding protein 1 (GBP1) as novel intra-cellular LPS sensor. Our cell-free and cell-based studies revealed that polymeric GBP1 attaches initially to the bacterial surface via direct interaction with LPS before transforming into a protein coat enclosing the bacterial cell. We not only observed that this GBP1 coatomer affects the localization and function of an outer membrane virulence factor, but also discovered, that surfactant GBP1 breaks down the protective outer membrane barrier for antimicrobial recognition and killing. How the GBP1 coatomer interferes with the integrity of the bacterial envelope remains largely unknown and will be addressed in this work. By combining biochemical, cell biology, and microbiology techniques, we will probe whether the GBP1 coatomer affects (Aim 1) physical properties and (Aim 2) composition of the outer membrane, and (Aim 3) determine whether GBP1 interferes with outer membrane virulence factors directly. This research proposal not only promises immediate mechanistic and conceptual insights into how the cytosolic host defense protein GBP1 breaks down the bacterial envelope for antimicrobials such as cell-intrinsic immune factors and last-resort antibiotics. Results of our studies also lay the foundation to future work, in which we intend to use our knowledge in host-pathogen-drug interactions between LPS surfactants, bacterial pathogens, and antibiotics to develop novel strategies to combat multidrug-resistant bacteria, an emerging global health threat.

• DFG Programme: Research Grants