Abstract
The strong age dependency of neonatal systemic infection with Escherichia coli K1 can be replicated in the neonatal rat. Gastrointestinal (GI) colonization of two-day-old (P2) rats leads to invasion of the blood within 48 h of initiation of colonization; pups become progressively less susceptible to infection over the P2-P9 period. We show that, in animals colonized at P2 but not at P9, E. coli K1 bacteria gain access to the enterocyte surface in the mid-region of the small intestine and translocate through the epithelial cell monolayer by an intracellular pathway to the submucosa. In this region of the GI tract, the protective mucus barrier is poorly developed but matures to full thickness over P2-P9, coincident with the development of resistance to invasion. At P9, E. coli K1 bacteria are physically separated from villi by the mucus layer and their numbers controlled by mucus-embedded antimicrobial peptides, preventing invasion of host tissues.
Highlights
Escherichia coli is a leading cause of early- and late-onset neonatal sepsis; a high proportion of strains responsible for these life-threatening infections express the K1 capsule, an anti-phagocytic, polysialic acid homopolymer that facilitates survival in the bloodstream and is closely associated with the capacity to invade and cause disease in the central nervous system of susceptible infants[1, 2]
We previously determined that oral administration of ~106 CFU E. coli A192PP to P2, P5 and P9 pups resulted in a stable GI tract E. coli K1 population of 107–108 bacteria/g GI tissue[16]
There were no significant differences between the age groups at any sampling point over a 120 h period, but there were relatively more E. coli K1 in the colon of P9 compared to P2 pups
Summary
Escherichia coli is a leading cause of early- and late-onset neonatal sepsis; a high proportion of strains responsible for these life-threatening infections express the K1 capsule, an anti-phagocytic, polysialic acid homopolymer that facilitates survival in the bloodstream and is closely associated with the capacity to invade and cause disease in the central nervous system of susceptible infants[1, 2]. Substantial changes in developmental gene expression occur between two (P2) and nine (P9) days postpartum[16], including upregulation of genes encoding antimicrobial α-defensin peptides: following E. coli K1 GI colonization, α-defensin genes defa[24] and defa-rs[1] were found to be up-regulated in P9, but not P2, pups. Developmental expression of Tff[2] was massively dysregulated in P2 but not P9 rats and was accompanied by a decrease in the amount of colonic Muc[216] These changes will compromise innate GI defenses in susceptible P2 animals but enhance protection in older resistant pups and contribute to the age-related susceptibilities to E. coli K1 infection
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