Insulin modulates the inflammatory granulocyte response to streptococci via phosphatidylinositol 3-kinase.

Group B streptococci (GBS; Streptococcus agalactiae) are a major cause of invasive infections in newborn infants and in patients with type 2 diabetes. Both patient groups exhibit peripheral insulin resistance and alterations in polymorphonuclear leukocyte (PML) function. In this investigation, we studied the PML response repertoire to GBS with a focus on TLR signaling and the modulation of this response by insulin in mice and humans. We found that GBS-induced, MyD88-dependent chemokine formation of PML was specifically downmodulated by insulin via insulin receptor-mediated induction of PI3K. PI3K inhibited transcription of chemokine genes on the level of NF-κB activation and binding. Insulin specifically modulated the chemokine response of PML to whole bacteria, but affected neither activation by purified TLR agonists nor antimicrobial properties, such as migration, phagocytosis, bacterial killing, and formation of reactive oxygen species. The targeted modulation of bacteria-induced chemokine formation by insulin via PI3K may form a basis for the development of novel targets of adjunctive sepsis therapy.

NO is a macrophage autonomous modifier of the cytokine response to streptococcal single-stranded RNA.

Group B streptococci, a major cause of sepsis, induce inflammatory cytokines in strict dependence on bacterial ssRNA and the host molecules MyD88 and UNC-93B. In this study, we show that NO plays an important role in Group B streptococci-induced transcriptional activation of cytokine genes. Phagocytosis induced NO in a MyD88-dependent fashion. In turn, NO propagated the acidification of phagosomes and the processing of phagosomal bacterial nucleic acids and was required for potent transcriptional activation of cytokine genes by streptococci. This NO-dependent amplification loop has important mechanistic implications for the anti-streptococcal macrophage response and sepsis pathogenesis.

Induction and termination of inflammatory signaling in group B streptococcal sepsis.

SUMMARY: Group B streptococcus (GBS) is part of the normal genital and gastrointestinal flora in healthy humans. However, GBS is a major cause of sepsis and meningitis in newborn infants in the Western world and an important pathogen in many developing countries. The dissection of the host response to GBS may increase the general understanding of innate immunity in sepsis, because newborn infants lack a sufficient adaptive response. Inflammatory signal induction in macrophages by GBS seems largely preserved in newborn infants, as shown both in vitro and in vivo. The engagement of Toll-like receptor 2 (TLR2) by lipoproteins and a myeloid differentiation factor 88 (MyD88)--dependent pathway induced by GBS cell wall are both important in this context. TLR2 activation of microglia by GBS induces neuronal damage, which might account for the high morbidity of GBS meningitis. At the same time, TLR2 mediates activation-induced cell death (AICD), a process involved in the containment of inflammation. In newborn infants, AICD and anti-bacterial polymorphonuclear leukocyte activity appears to be compromised. Accordingly, neonatal aberrations in the pathogen-specific negative control of inflammatory signaling are likely to contribute to excessive inflammation and neurological sequelae in GBS sepsis and meningitis.

TLR2 and caspase-8 are essential for group B Streptococcus-induced apoptosis in microglia.

Microglia, the resident innate immune cells of the CNS, detect invading pathogens via various receptors, including the TLR. Microglia are involved in a number of neurodegenerative diseases in which their activation may be detrimental to neurons. It is largely unknown how this potentially deleterious action can be countered on a cellular level. We previously found that the interaction of TLR2 with group B Streptococcus (GBS), the most important pathogen in neonatal bacterial meningitis, activates microglia that in turn generate neurotoxic NO. We report in this study that GBS not only activates microglia, but also induces apoptosis in these cells via TLR2 and the TLR-adaptor molecule MyD88. Soluble toxic mediators, such as NO, are not responsible for this form of cell death. Instead, interaction of GBS with TLR2 results in formation and activation of caspase-8, a process that involves the transcription factor family Ets. Whereas caspase-8 plays an essential role in GBS-induced microglial apoptosis, caspase-3 is dispensable in this context. We suggest that TLR2- and caspase-8-mediated microglial apoptosis constitutes an autoregulatory mechanism that limits GBS-induced overactivation of the innate immune system in the CNS.