Host lipid landscape remodeling by Staphylococcus aureus and its impact on infection and inflammation.

• Applicant: Dr. Arnaud Kengmo Tchoupa
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563206372

Lipids play multiple roles at the host – pathogen interface, including signaling to activate immune responses or binding to bacteria to inhibit their growth. Bacteria colonizing mucosal surfaces and the skin have unsurprisingly evolved several strategies to manipulate host-derived lipids. These strategies are not yet fully understood and disentangling them may open new avenues to combat multidrug-resistant bacteria. Recently, we have uncovered that Staphylococcus aureus, an important human pathogen, utilizes its lipase Lip2 to esterify and thereby detoxify host-derived antimicrobial fatty acids with cholesterol. This newfound role and promiscuity of Lip2 strongly suggested that this enzyme may reshape the environmental lipid landscape during bacterial colonization and invasion of the host. In vitro, we indeed observed that Lip2-expressing bacteria produced wax esters, and fatty acid esters of hydroxy fatty acids (FAHFAs). While wax esters are important structural components of mammalian skin, FAHFAs are G-protein-coupled receptor agonists (GPR40 and GPR120), which have recently been characterized as anti-diabetic and anti-inflammatory. However, the potential role of FAHFAs in bacterial colonization and infection has not been investigated so far. Additionally, we discovered Lip2-catalyzed biosynthesis of a hitherto unknown class of lipids: hydroxy fatty acid esters of hydroxy fatty acids (HFAHFAs), with unclear functions in the host – microbe crosstalk. In this research proposal, we aim to dissect the molecular determinants and mechanisms of S. aureus-mediated production of FAHFAs and HFAHFAs, which is unprecedented in bacteria. Furthermore, we will leverage a murine infection model with lipase-proficient and -deficient bacteria to investigate bacteria-elicited synthesis of FAHFAs and HFAHFAs in vivo. In this in vivo model, we will also explore the extent to which FAHFAs and HFAHFAs alleviate inflammation to enable the proliferation of S. aureus. For a better mechanistic understanding of the signaling cascades triggered by FAHFAs and/or HFAHFAs, we will analyze cytokine release and/or GPR40/120 activation by established cell lines and primary cells from mice or healthy volunteers upon incubation with S. aureus or its exoproducts. The roles of these lipids in the intracellular survival of S. aureus will also be investigated. Taken together, the proposed experiments are tailored to uncover and characterize underappreciated lipid mediators used by S. aureus – and most likely other bacterial members of the microbiome – to blunt innate immune recognition of their otherwise highly proinflammatory microbial associated molecular patterns.

• DFG Programme: Research Grants