Vertically transferred antibodies protect babies from Escherichia coli infection

About This Grant

Abstract. Newborn babies are highly vulnerable to infection by normally innocuous commensal bacteria. This includes the ubiquitous Gram-negative bacterium Escherichia coli, which is the leading cause of neonatal sepsis. Our preliminary studies show susceptibility in this early life developmental window extends to mice, since neonatal mice uniformly succumb to even low dose infection. Despite shared vulnerability, an interesting distinction is the uniform susceptibility of neonatal mice to E. coli infection – which is in sharp contrast to only 30-50 cases in every 100,000 live birth human babies. We reasoned that if the newborn status alone confers susceptibility to E. coli infection, this distinction begs the question as to why invasive E. coli infection does not occur more frequently in human babies given their universal early life exposure to this ubiquitous commensal. In other words, instead of investigating why babies are susceptible to E. coli, perhaps the more relevant question is why infection does not occur more frequently beyond this small fraction of all E. coli exposed human babies. In this regard, E. coli colonization represents an inherent, but underappreciated, difference between humans and standard laboratory mice. Commensal E. coli can be found in the feces of nearly all individuals, but is completely devoid in mice reared under specific pathogen free laboratory conditions. Our ongoing studies show high titer anti-E. coli “natural” antibodies in healthy adult individuals, their persistence during pregnancy and neonatal cord blood specimens. This “natural” classification indicates anti-E. coli antibodies are physiologically primed by commensal colonization, without infection or immunization. Comparatively mice devoid of commensal E. coli show only background anti-E. coli IgG titers, which rise sharply after experimental colonization using non-pathogenic probiotic strains such as Nissle 1917. In turn, anti-E. coli IgG is efficiently transferred from Nissle colonized mice to their neonatal offspring, which overrides their susceptibility to E. coli infection. Thus, our overall hypothesis (scientific premise) is that vertically transferred maternal immunity overrides the inherent susceptibility of newborn infants to E. coli. By extension, babies that do develop E. coli infection have quantitative or qualitative defects in vertically transferred anti-E. coli immunity. This groundbreaking hypothesis is supported by ongoing studies showing reduced anti-E. coli IgG levels in newborn blood spot specimens of babies that develop E. coli sepsis, and will be further investigated in combination with the aforementioned preclinical platform of E. coli colonization primed immunity that extends to vertically transferred protection in neonatal offspring through the following aims: investigate anti-E. coli antibody titers, along with infant variables including sex and gestational age in vertically transferred IgG function (Aim 1), establish the specific Fc receptor (FcR) and neonatal cell type(s) responsive to IgG that protect against E. coli infection (Aim 2), and evaluate breadth of protection primed by Nissle colonization against E. coli strains that cause neonatal infection (Aim 3).