The contribution of Bruton's tyrosine kinase to innate host defense during bacterial infections

Acute bacterial infections can cause pneumonia and peritonitis, and in the worst case can lead to sepsis, a dysregulated host response to infection that may advance in life-threatening organ dysfunction. Bruton’s tyrosine kinase (Btk) is an intracellular protein, expressed by almost all immune cells, that interacts with several key components involved in the signaling pathways of a variety of receptors and thereby plays a versatile role in the regulation of diverse immune cell effector functions. Btk deficiency results in susceptibility to certain bacterial infections, which has mainly been attributed to the essential role of Btk in B cell development and reduced antibody levels. The role of Btk in myeloid cells during host immunity against bacterial infection, however, remains controversial.
The aim of this thesis was to determine the contribution of Btk to innate host defense during bacterial pneumonia, peritonitis and during sepsis. Therefore, we performed studies with complete and cell-specific Btk deficient mice and well-established models induced by clinically relevant, virulent bacteria, including Streptococcus pneumoniae, Klebsiella pneumoniae and Escherichia coli.
Our studies revealed that Btk in B cells does not unequivocally contribute to innate immunity during bacterial pneumonia, whereas Btk in neutrophils was essential for host defense. In contrast, Btk was detrimental for host defense during bacterial peritonitis. In addition, we demonstrated that pharmacological inhibition of Btk ameliorates lung inflammation during antibiotic-treated bacterial pneumonia.
In conclusion, this thesis provides new insight in the in vivo role of Btk in innate host defense during bacterial pneumonia, peritonitis and sepsis.