Alpha-toxin elicited CX3CL1-release via ADAM10 in Staphylococcus aureus pneumoniaimpairs bactericidal function of human monocytes

Mairpady Shambat, S.; Chen, P.; Barilla, R. M.; Huemer, M.; Snaell, J.; Welin, A.; Cohen, T. S.; Takahashi, V.; Berry, S. B.; Gomez-Mejia, A.; Schweizer, T. A.; Cunoosamy, D. M.; Cajander, S.; Lourdaa, M.; Ozenci, V.; Marques Maggio, E.; Schuepbach, R. A.; Stralin, K.; Zinkernagel, A. S.; Norrby-Teglund, A.; Svensson, M.

doi:10.1101/2023.09.17.554633

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bioRxiv · 10.1101/2023.09.17.554633

Alpha-toxin elicited CX3CL1-release via ADAM10 in Staphylococcus aureus pneumoniaimpairs bactericidal function of human monocytes

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Abstract

Staphylococcus aureus is an important human pathogen causing severe invasive infections. Pathogenesis is attributed to a wide array of virulence factors, including several potent exotoxins such as the pore-forming alpha-toxin. In this study, we found that patients with S. aureus respiratory tract infections had elevated CX3CL1 levels in airway fluid and plasma. Using humanized organotypic lung models, we observed that stimulation of lung epithelium with alpha-toxin induce an intensified CX3CL1 expression apically in the epithelium as well as the release of CX3CL1. Blocking alpha-toxin or ADAM10 activity in organotypic lung using an alpha-toxin-blocking antibody or a specific ADAM-10 inhibitor confirmed their role in modulating CX3CL1 cleavage and release. Analyses of CD14+ human monocytes in combination with a CX3CR1 inhibitor revealed that alpha-toxin-mediated CX3CL1 release induce CX3CL1-dependent chemotaxis. In line with these data, lung tissue from patients with S. aureus respiratory tract infection showed elevated CX3CL1 and CD14 staining as compared to tissue from patients with non-infectious lung diseases. Functional studies of monocytes showed that CX3CL1 released by lung models resulted in upregulated CD83 and downregulated CD86, as well as impaired killing of phagocytosed S. aureus. Furthermore, stimulation of monocytes with soluble CX3CL1 hampered their reactive-oxygen and nitric-oxide production. Taken together, our data show that S. aureus triggers the release of lung epithelial CX3CL1; a process found to be dependent on the alpha-toxins effect on ADAM10 mediating cytotoxicity and resulting in impaired monocyte phagocytic killing. Hence, we identify an immunomodulatory effect of alpha-toxin involving the CX3CL1-ADAM10 axis extending beyond the cytolysis function.

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Mairpady Shambat, S., Chen, P., Barilla, R. M., Huemer, M., Snaell, J., Welin, A., Cohen, T. S., Takahashi, V., Berry, S. B., Gomez-Mejia, A., Schweizer, T. A., Cunoosamy, D. M., Cajander, S., Lourdaa, M., Ozenci, V., Marques Maggio, E., Schuepbach, R. A., Stralin, K., Zinkernagel, A. S., Norrby-Teglund, A., Svensson, M.. 2023-09-18. Alpha-toxin elicited CX3CL1-release via ADAM10 in Staphylococcus aureus pneumoniaimpairs bactericidal function of human monocytes. https://doi.org/10.1101/2023.09.17.554633

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