Group B streptococci induce proinflammatory responses via a protein kinase D1-dependent pathway (INM7P.351)

Abstract

Abstract Group B streptococci (GBS) are one of the leading causes of life-threatening sepsis in neonates. Despite intervention with antibiotic therapy, the incidence of lethality is high among GBS-infected infants. The clinical symptoms of sepsis are related to the host-pathogen interaction and exaggerated proinflammatory cytokine production during the process via pathways dependent on Toll-like receptors (TLRs). Over the last few years, it has become evident that protein kinase D1 (PKD1) plays a significant role in the inflammatory process mediated by TLRs. However, it is currently unknown whether PKD1 is activated, and contributes to proinflammatory responses induced by live or antibiotic-killed GBS. In the present study, we found that both live and antibiotic-killed GBS induce activation of PKD1 that is dependent on the TLR signaling adaptor MyD88 and its downstream kinase IRAK1, but not TRAF6. Inhibition of PKD using a pharmacological inhibitor revealed that PKD1 is indispensable for GBS-mediated expression of various cytokines/chemokines in vitro and in vivo. Furthermore, systemic administration of PKD inhibitor protects D-galactosamine-sensitized mice from shock-mediated death caused by antibiotic-killed GBS. Our findings imply that PKD1 is one of the critical factors that play a regulatory role in GBS-induced proinflammatory reactions, and inhibition of PKD1 activation together with antibiotic treatment in GBS-infected neonates might be an effective way to control GBS diseases.