Induction and termination of inflammatory signaling in group B streptococcal sepsis

Abstract

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, since 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.

Infection and Cellular Defense Dynamics in a Novel 17β-Estradiol Murine Model of Chronic Human Group B Streptococcus Genital Tract Colonization Reveal a Role for Hemolysin in Persistence and Neutrophil Accumulation

“…Numbers of PMNs steadily increased in the surface mucosa of the genital tract in response to GBS over time, according to swab-smear analysis and histopathology, and peaked between days 30 and 60. This influx of PMNs parallels an infiltrate of PMNs observed in GBS neonatal disease (26). Precisely when this influx wanes in the genital tract during chronic GBS colonization is unclear because we concluded our assays at 90 d. The small increase in PMN responses at day 30 in control mice observed in our study likely relates to the invasive nature of the challenge procedure and the trauma of inoculation into the vaginal vault.…”

“…The contribution of maternal Abs to the protection of newborns against GBS disease is discussed elsewhere in relation to pathogenesis (26). GBS b-hemolysin contributes to pathogenesis (27,28), but the role of this virulence factor in the female genital tract is essentially unknown.…”

The NOD2 receptor modulates the cytokine response but does not alter the clinical outcome of Group B Streptococcus-infected mice

“…Compared to the results reported in the study of Costa et al [32] , we concluded that NOD2 is not as relevant as NLRP3, at least in adult mice. These findings represent an important step in understanding how GBS interacts with immune cells and confirm the hypothesis that GBS use complex TLR-dependent [33] , NLRP3-dependent [32] , NOD2-dependent in addition to TLR/NOD2-independent pathways to modulate host immune responses.…”

Maternal inflammation modulates infant immune response patterns to viral lung challenge in a murine model

“…Fetal exposure to maternal inflammation may induce a priming effect on the infant immune system, setting the stage for exaggerated systemic inflammatory responses to localized infection, such as in the lungs. Thus, antenatal exposure to subclinical inflammatory processes could help explain the often severe systemic inflammatory responses and related mortality observed in human preterm infants with pneumonia or other organ-restricted infections (32,33). Although further study is needed to characterize the underlying mechanisms, the present information provides new knowledge in understanding how fetal exposure to inflammation may adversely influence postnatal immune function.…”