Induction and termination of inflammatory signaling in group B streptococcal sepsis

Abstract

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.

Fig. 1. Negative regulation of TLR2-dependent signaling

Bacterial lipoproteins directly interact with the TLR2/1 or TLR2/6 dimer. Then MAL/TIRAP is recruited to PIP2 in the plasma membrane through its PIP2-binding domain. MAL/TIRAP links the TLR2-dimer to MyD88, which activates a complex downstream signaling cascade. A parallel event upon TLR2 activation is the tyrosine phosphorylation (aa 86 and 187) of MAL/TIRAP by Bruton's tyrosine kinase, which leads to NFκB p65 serine phosphorylation. TLR2 signaling is terminated through a negative feedback loop which comprises SOCS-1. SOCS-1 recognizes the MAL/TIRAP via its PEST domain, polyubiquitinates MAL/TIRAP, and targets it to 26S proteasome-dependent degradation.