Spleen Tyrosine Kinase as a Target Therapy for Pseudomonas aeruginosa Infection

Abstract

Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase which associates directly with extracellular receptors, and is critically involved in signal transduction pathways in a variety of cell types for the regulation of cellular responses. SYK is expressed ubiquitously in immune and nonimmune cells, and has a much wider biological role than previously recognized. Several studies have highlighted SYK as a key player in the pathogenesis of a multitude of diseases. Pseudomonas aeruginosa is an opportunistic gram-negative pathogen, which is responsible for systemic infections in immunocompromised individuals, accounting for a major cause of severe chronic lung infection in cystic fibrosis patients and subsequently resulting in a progressive deterioration of lung function. Inhibition of SYK activity has been explored as a therapeutic option in several allergic disorders, autoimmune diseases, and hematological malignancies. This review focuses on SYK as a therapeutic target, and describes the possibility of how current knowledge could be translated for therapeutic purposes to regulate the immune response to the opportunistic pathogen P. aeruginosa.

Keywords: Cystic fibrosis; Cystic fibrosis transmembrane conductance regulator; Infection; Inflammation; Pseudomonas aeruginosa; Small molecule inhibitor; Spleen tyrosine kinase.

Fig. 1

Structure of SYK protein: a schematic diagram of the linear structure of SYK with the tyrosines marked that are phosphorylated after activation.

Fig. 2

General mechanism of SYK activation and SYK-mediated signaling: a pathway demonstrating the involving of downsignaling associated with SYK activation. AKT, protein kinase B; ERK, extracellular signal-regulated kinase; GPCRs, G protein-coupled receptors; IL-1R, interleukin-1 receptor; JNK, c-Jun N-terminal kinase; PM, plasma membrane; TNFR, tumor necrosis factor receptor.

Fig. 3

Effect of altered CFTR function in cystic fibrosis (CF) and promotion of chronic pulmonary infection. Defective ion exchanges in the airway epithelium lead to bacterial colonization and inflammation in the lungs of CF patients.