Codevelopment of Microbiota and Innate Immunity and the Risk for Group B Streptococcal Disease

Abstract

The pathogenesis of neonatal late-onset sepsis (LOD), which manifests between the third day and the third month of life, remains poorly understood. Group B Streptococcus (GBS) is the most important cause of LOD in infants without underlying diseases or prematurity and the third most frequent cause of meningitis in the Western world. On the other hand, GBS is a common intestinal colonizer in infants. Accordingly, despite its adaption to the human lower gastrointestinal tract, GBS has retained its potential virulence and its transition from a commensal to a dangerous pathogen is unpredictable in the individual. Several cellular innate immune mechanisms, in particular Toll-like receptors, the inflammasome and the cGAS pathway, are engaged by GBS effectors like nucleic acids. These are likely to impact on the GBS-specific host resistance. Given the long evolution of streptococci as a normal constituent of the human microbiota, the emergence of GBS as the dominant neonatal sepsis cause just about 50 years ago is remarkable. It appears that intensive usage of tetracycline starting in the 1940s has been a selection advantage for the currently dominant GBS clones with superior adhesive and invasive properties. The historical replacement of Group A by Group B streptococci as a leading neonatal pathogen and the higher frequency of other β-hemolytic streptococci in areas with low GBS prevalence suggests the existence of a confined streptococcal niche, where locally competing streptococcal species are subject to environmental and immunological selection pressure. Thus, it seems pivotal to resolve neonatal innate immunity at mucous surfaces and its impact on microbiome composition and quality, i.e., genetic heterogeneity and metabolism, at the microanatomical level. Then, designer pro- and prebiotics, such as attenuated strains of GBS, and oligonucleotide priming of mucosal immunity may unfold their potential and facilitate adaptation of potentially hazardous streptococci as part of a beneficial local microbiome, which is stabilized by mucocutaneous innate immunity.

Keywords: Group B Streptococcus; S. agalactiae; cellular innate immunity; colonization; microbiome; sepsis.

Figure 1

Innate immune pathways manipulated by Group B Streptococcus. Depicted is the impact of GBS on type I interferons (IFN) (153, 155), Toll-like receptor (TLR) (10, 149), and inflammasome (151) pathways by secreted bacterial factors. The ectonucleotidase CdnP hydrolyzes bacterial cyclic dinucleotides which otherwise activate STING and IFN-β production (154). Hemolysin contributes as second signal to the NLRP3 inflammasome activation (152). The GBS hyaluronidase can degrade pro-inflammatory hyaluronan polymers during tissue injury which normally bind to TLR2 and the resulting fragments block TLR2 signaling in the host (157).

Figure 2

Stabilization of the mucocutaneous niche. During homeostasis, GBS colonizes the intestine of healthy infants. Macrophages and other immune cells guarantee barrier integrity by surveillance. Other commensal bacteria including streptococcal species form the niche. Disease can be preceded by multiple factors leading to dysbiosis, expansion of GBS and barrier disruption. Expression of virulence factors such as HvgA and β-toxin facilitate adhesion to epithelial cells and barrier disruption. Dissemination is often concurrent with mutations of the CovR/S virulence repressor.