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.

Gut and Lung Microbiota in Preterm Infants: Immunological Modulation and Implication in Neonatal Outcomes

“…Particularly, it is unknown how the colonization remains stable from the first contact with GBS until the disease onset. Also in this case, there are data that show as an aberrant codevelopment of microbiota and host immunity represent a risk for GBS LOS, rather than genetic variations in immune genes alone (112). Affected infants show a decreased presence of anaerobic Bacteroides and Bifidobacterium spp., while aerobic Enterobacteria appear to be increased, when compared to nonseptic twin controls (113).…”

The role of CNS macrophages in streptococcal meningoencephalitis

“…Next to the lethality of GBS meningoencephalitis (5–10%), long‐term neurologic impairment of variable degrees affects up to 30 to 70% of surviving infants . GBS has been cultured from breast milk of the nursing mother and the intestinal tract of individual infants before onset of LOD and meningitis in individual cases, which suggests that GBS is acquired through the intestinal route, yet this model remains somewhat speculative. The concept that GBS dissemination happens from the intestine to the CNS is supported by the study of Poyart et al., where intestinal GBS colonization in mice in the first three weeks of life led to CNS invasion and meningoencephalitis .…”

Novel Approaches to the Study of Neonatal Infections

“…In certain conditions, exposure to multiple factors (e.g., antibiotics and altered immunological responses at the gut mucosal-microbial interface) may lead to dysbiosis, which, in turn, would widen the niche of pathogenic bacteria and lead to pathogenic bacterial overgrowth, gut barrier disruption (that may be facilitated by virulence factors carried by colonizing strains), and, eventually, dissemination of the pathogenic microorganism to the bloodstream. 19 Confirmation that dysbiosis precedes sepsis in humans will be of maximal importance to support this hypothesis, especially for sepsis occurring in apparently healthy infants. Furthermore, future studies should focus on the identification of currently unknown factors causing dysbiosis, ultimately leading to pathogenic bacterial overgrowth and barrier disruption in home-discharged, apparently healthy infants with currently no identifiable risk factors.…”