A novel model to study neonatal Escherichia coli sepsis and the effect of treatment on the human immune system using humanized mice

Abstract

The human immune system in humanized mice responds to the infection, making them a suitable model to study neonatal E. coli sepsis and the immune response of the neonatal immune system. Treatment with Betamethasone could have potential negative long-term effects for the immune system of the child.

Humanized Mice as a Tool to Study Sepsis—More Than Meets the Eye

“…On a few occasions, humanized animals were employed to test certain compounds' effectiveness to modify sepsis's natural history. Ernst et al published two papers showing the effect of betamethasone and indomethacin in neonatal sepsis modeled by "immaturity" of the humanized mice immunity [25,26]. A third paper complemented these studies, showing a similar effect when a pathogen from Gram-positive bacteria stimulated neonatal cord mononuclear leukocytes [25,88].…”

“…However, it is useful to study essential immune responses allowing for precise manipulation of the kind and dose of pathogen used. Type of infected compartment of infection and host susceptibility are essential factors determining animal responses in the toxemia model [25,26].…”

“…Animals did not receive fluid resuscitation or antibiotics. Despite Hotchkiss's pioneering research, it is still surprising that it took over 15 years for the first study of septic shock in humanized mice to appear since the first introduction of this model in 1992 [26]. Further studies confirmed the secretion of TNFα, IL-6, and IL-10 in response to TLR-stimulation by PAMP in humanized mice [21,51].…”

“…Humanized mice were utilized to model neonatal sepsis in two studies from the same research group to demonstrate potential effect of prostaglandin and steroid modulators [25,26]. Pervasively, authors argued that imperfection of the human immune system in humanized mice equates to the "immature" immune system seen in neonates.…”

Mouse Models of Sepsis and Septic Shock

“…Moreover, a vast panel of genetically modified mice with changes in immune system components is available and provides additional opportunities to investigate the molecular mechanisms involved in the pathogenesis of sepsis. Humanized mouse strains are important to use more broadly to experimentally model sepsis because the pathology development in humans is better reproduced in such models [134,[141][142][143][144][145]. However, it should be noted that immune system components are primarily subject to humanization, while the nervous system, the epithelium, the endothelium, and metabolic pathways important for the development of sepsis remain mouse [72,[146][147][148][149].…”