Humanized Mice, a New Model To Study the Influence of Drug Treatment on Neonatal Sepsis

Abstract

cBacterial infection with group B Streptococcus (GBS) represents a prominent threat to neonates and fetuses in the Western world, causing severe organ damage and even death. To improve current therapeutic strategies and to investigate new approaches, an appropriate in vivo model to study the immune response of a human immune system is needed. Therefore, we introduced humanized mice as a new model for GBS-induced sepsis. Humanized mice feature deficiencies similar to those found in neonates, such as lower immunoglobulin levels and myeloid cell dysfunction. Due to the husbandry in specific-pathogen-free (SPF) facilities, the human immune cells in these mice also exhibit a naive phenotype which mimics the conditions in fetuses/ neonates. Following infection, cytokine release and leukocyte trafficking from the bone marrow to the lymphoid organ (spleen) and into the peritoneum (site of infection) as well as bacterial spreading and clearance were traceable in the humanized mice. Furthermore, we investigated the effects of betamethasone and indomethacin treatment using this novel sepsis model. Although both drugs are commonly used in perinatal care, little is known about their effects on the neonatal immune system. Treatment of infected humanized mice not only induced the reduction of human leukocytes in the spleen but also increased the bacterial load in all analyzed organs, including the brain, which did not show infiltration of live GBS in untreated controls. These studies demonstrate the utility of the humanized mice as a new model to study an immature human immune response during bacterial infection and allow the investigation of side effects induced by various treatments.

Humanized Mouse Models of Clinical Disease

“…Sepsis is a whole body inflammatory condition that can induce death through cytokine storm and apoptosis of lymphocytes (69, 70). Cecal ligation and puncture (CLP) in HSC-engrafted NSG mice led to increased inflammatory cytokines and lymphocyte apoptosis (70).…”

Abandon the Mouse Research Ship? Not Just Yet!

“…We suggest multiple animal models should be considered for basic research and preclinical testing of therapeutics. The remarkable capability of contemporary science has opened many new investigative avenues such as emergence of humanized mice (111, 112, 113) and access to a growing selection of recombinant inbred mouse strains (with specific defined genetic traits) from the Collaborative Cross Project (114; 115). Yet, whereas using inbred mice for basic research remains important to advancing knowledge and may allow much more nuanced investigation of gene environment and gene-pathogen interactions, the efficacy testing of beneficial treatments should be tested in outbred mice as well.…”

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

“…Regular mice are widely used as sepsis models even though the murine and the human immune system differ in at least 67 known features. Due to all these advantages, we used humanized mice to generate an animal model for neonatal GBS sepsis 21 and now for a novel model for neonatal E. coli sepsis. 16 The fact that the human immune system in these animals is deficient in certain aspects makes it an even more suitable model for studying neonatal sepsis, as neonates, especially preterm infants, feature similar deficiencies.…”

“…14 Monocytes and macrophages are essential regulators of the immune response by expressing modulating cytokines. 19,20 Human neutrophils are markedly underrepresented in the peripheral blood and the bone marrow of humanized mice, 21 indicating a small neutrophil storage pool. 15 The animal model we chose not only allowed for analyzing the pathogenesis of the E. coli infection but also the effect of both infection and treatment on the human immune system.…”