Abstract / Summary
Abstract Streptococcus agalactiae (Group B Streptococcus, GBS) is a major cause of neonatal sepsis and is increasingly associated with invasive infections in non-pregnant adults. GBS produces a cell wall-associated lipid toxin, the pigment (granadaene), a key virulence factor with cytotoxic and immunomodulatory properties. While its effects on several immune cells have been described, its impact on human dendritic cells remains largely unknown. Here, the role of the GBS pigment during infection of human monocyte-derived dendritic cells (moDCs) was assessed. Infection with pigmented GBS induced rapid cell death, characterized by early loss of mitochondrial membrane potential and phosphatidylserine exposure, culminating in membrane disruption. Inhibition of canonical cell death pathways indicated that moDC death occurs predominantly via a caspase-independent, mitochondria-driven mechanism, with caspase-8 activity enhancing the process. Blocking phagocytosis did not reduce cytotoxicity, whereas restriction of bacteria to the intracellular compartment markedly diminished cell death, indicating that the pigment primarily acts extracellularly. Following removal of extracellular bacteria and 24-h incubation, infected moDCs remained largely viable and exhibited comparable maturation and cytokine responses, regardless of whether the infecting bacteria expressed the pigment. Together, these findings indicate that pigment-dependent cytotoxicity in moDC infections is mediated by extracellular GBS.