Regulation and function of Sphingosine 1-phosphate receptors in the brain vasculatures during bacterial meningitis

• Applicant: Dr. Ingo Fohmann
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; General Genetics and Functional Genome Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 581137571

Bacterial meningitis is a life-threatening disease with approximately 2.5 million infections and 200,000 fatalities annually. While the case numbers are declining due to efficient vaccination campaigns, neonatal meningitis still poses a significant health threat, since vaccine strategies do not include newborns. Infection with meningitic Escherichia coli, a main cause of neonatal meningitis, therefore, is an unmet health risk for newborns. The fatality rate is high, and survivors often suffer from severe sequalae, even if the correct diagnose and respective antibiotic treatment is promptly initiated. It is hence essential to improve our knownledge about the pathomechanisms of meningitic Escherichia coli to develop strategies for the adjuvant therapy of neonatal meningitis. In health, the brain is shielded from blood-borne pathogens by a tight vascular barrier, also known as the blood-brain barrier (BBB). Sphingosine 1-phosphate receptors (S1PRs) are promising targets for adjuvant therapy of different brain pathologies due to their regulatory role in BBB integrity. Bacterial infections however disrupt the S1PR expression pattern in the BBB. Additionally, S1PR2 expression is essential for draining lymphatic function and recent studies demonstrate that impaired draining of cerebrospinal fluid (CSF) over the meningeal lymphatics leads to a poor prognosis of meningitis. We hypothesize that S1PRs of the brains blood and lymphatic vasculature are major determinants of brain pathologies and that the S1PR expression pattern can be targeted by adjuvant therapy during neonatal meningitis. In the presented project we aim to identify the key transcriptional regulators, which lead to a disruption of the S1PR expression pattern in the brain vasculatures. Preliminary experiments showed that the infection with meningitic Escherichia coli changes the expression of S1PRs and S1PR regulator CD69 in vivo. As a next step, S1PR dysregulation hence will be studied in vivo with intravital microscopy of infected neonatal wild type or S1PR transgenic mice. ATAC-seq will be leveraged to identify cis regulatory elements causing S1PR dysregulation. A combination of AAV- and CRISPR/Cas9-based disruption of those elements in vivo will shed light on their function and their therapeutic potential for the therapy of meningitis. In summary, this project aims to unravel the epigenetic regulation of S1PRs as a determinant of neonatal meningitis and to establish S1PRs as a target for adjuvant therapy.

• DFG Programme: Fellowship
• International Connection: USA
• Host: Professor Timothy T. Hla, Ph.D.