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.
Highlights
Neonatal sepsis occurs as two distinct clinical entities either in the first 72 h of life as early-onset disease (EOD), resulting from in utero or intrapartum infection, or during the following 3 months as late-onset sepsis (LOD)
Antibiotics can affect the composition of the microbiome in many ways, including the depletion of competitive microbes, a delay in immune cell maturation and dysbiosis, all of which widen the niche for pathogenic bacteria
The challenge to understand and prevent neonatal Group B Streptococcus (GBS) sepsis comprises (i) the control of GBS transmission during and immediately after birth leading to EOD and (ii) the subs equent control of GBS as a mucocutaneous colonizer, when failure results in LOD
Summary
Neonatal sepsis occurs as two distinct clinical entities either in the first 72 h of life as early-onset disease (EOD), resulting from in utero or intrapartum infection, or during the following 3 months as late-onset sepsis (LOD). In EOD, the size and deposition site, e.g., the lung, of the GBS inoculum may be decisive factors It is unresolved why GBS establishes as a harmless mucocutaneous colonizer in approximately 10% of infants in the first weeks of life, and overcomes epithelial barriers and cellular innate immunity only in less than one in thousand infants to cause LOD. ST-17 shows an elevated disease-tocolonization ratio in EOD and LOD, i.e., it causes more cases of invasive disease than expected from its colonization rate of pregnant women [28,29,30] These observations, together with the characteristic expression of several virulence factors, have led to the term of a “hypervirulent” strain. For further detailed descriptions about GBS virulence factors, we refer to recent reviews [36, 37]
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