Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, United States
Lamyaa Shaban
Graduate Program in Molecular Microbiology, Tufts Graduate School of Biomedical Sciences, Boston, United States
Matthias Mack
Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
Kenneth D Swanson
Brain Tumor Center and Neuro-Oncology Unit, Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, United States
Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, United States; Department of Immunology, School of Medicine, Tufts University, Boston, United States
David B Sykes
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, United States; Graduate Program in Molecular Microbiology, Tufts Graduate School of Biomedical Sciences, Boston, United States; Department of Molecular Biology and Microbiology, School of Medicine, Tufts University, Boston, United States
Klebsiella pneumoniae is a respiratory, blood, liver, and bladder pathogen of significant clinical concern. We show that the adaptor protein, SKAP2, is required for protection against K. pneumoniae (ATCC 43816) pulmonary infections. Skap2-/- mice had 100-fold higher bacterial burden when compared to wild-type and burden was controlled by SKAP2 expression in innate immune cells. Skap2-/- neutrophils and monocytes were present in infected lungs, and the neutrophils degranulated normally in response to K. pneumoniae infection in mice; however, K. pneumoniae-stimulated reactive oxygen species (ROS) production in vitro was abolished. K. pneumoniae-induced neutrophil ROS response required the activity of SFKs, Syk, Btk, PLCγ2, and PKC. The loss of SKAP2 significantly hindered the K. pneumoniae-induced phosphorylation of SFKs, Syk, and Pyk2 implicating SKAP2 as proximal to their activation in pathogen-signaling pathways. In conclusion, SKAP2-dependent signaling in neutrophils is essential for K. pneumoniae-activated ROS production and for promoting bacterial clearance during infection.
