Sphingosine kinase 1/S1P receptor signaling axis is essential for cellular uptake of Neisseria meningitidis in brain endothelial cells.
Ingo FohmannAlina WeinmannFabian SchumacherSimon PetersAgata PrellCynthia WeigelSarah SpiegelBurkhard KleuserAlexandra Schubert-UnkmeirPublished in: PLoS pathogens (2023)
Invasion of brain endothelial cells (BECs) is central to the pathogenicity of Neisseria meningitidis infection. Here, we established a key role for the bioactive sphingolipid sphingosine-1-phosphate (S1P) and S1P receptor (S1PR) 2 in the uptake process. Quantitative sphingolipidome analyses of BECs infected with N. meningitidis revealed elevated S1P levels, which could be attributed to enhanced expression of the enzyme sphingosine kinase 1 and its activity. Increased activity was dependent on the interaction of meningococcal type IV pilus with the endothelial receptor CD147. Concurrently, infection led to increased expression of the S1PR2. Blocking S1PR2 signaling impaired epidermal growth factor receptor (EGFR) phosphorylation, which has been shown to be involved in cytoskeletal remodeling and bacterial endocytosis. Strikingly, targeting S1PR1 or S1PR3 also interfered with bacterial uptake. Collectively, our data support a critical role of the SphK/S1P/S1PR axis in the invasion of N. meningitidis into BECs, defining a potential target for adjuvant therapy.
Keyphrases
- epidermal growth factor receptor
- endothelial cells
- tyrosine kinase
- poor prognosis
- small cell lung cancer
- protein kinase
- binding protein
- advanced non small cell lung cancer
- cell migration
- resting state
- high glucose
- long non coding rna
- drug delivery
- machine learning
- cystic fibrosis
- vascular endothelial growth factor
- cerebral ischemia
- climate change
- single cell
- nk cells
- human health