Miller Jernelle C, Choi Myeongjin, Zhao Zhiyong, Mushrush Ember M, Legesse Teklu B, Cross Alan S, Baliban Scott M, Tennant Sharon M
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Microbiol Spectr. 2025 Sep 2;13(9):e0069725. doi: 10.1128/spectrum.00697-25. Epub 2025 Aug 1.
is a major cause of neonatal sepsis in low- to middle-income countries. With the proportion of multidrug-resistant strains increasing globally and the lack of novel antibiotics in the pipeline, vaccination to prevent infections due to is an alternative strategy to antibiotics. Several vaccines are currently in development; however, there are no small animal models of -associated neonatal sepsis that can be used to evaluate vaccine efficacy. Therefore, we developed and characterized a neonatal murine model of infection. We found that neonatal C57BL/6 mice were highly susceptible to B5055, a serotype O1:K2 hypervirulent strain, via peroral inoculation, and the susceptibility of mice to infection was age and dose dependent. Mice aged 2-3 days consistently exhibited 88%-100% mortality when infected with 10-10 colony-forming units of B5055. This susceptibility progressively decreased during the neonatal period such that B5055 at this dose was avirulent in 10-day-old and older C57BL/6 mice following peroral administration. Two-day-old mice were bacteremic as early as 2 h post-infection, which was accompanied by systemic dissemination of beyond the gastrointestinal tract into the brain, liver, lungs, and spleen. However, only the liver and lungs displayed inflammatory infiltrate around the portal tract and neutrophilic exudate in the alveoli and air spaces, when compared to uninfected mice, which showed no pathological effects. Collectively, these results show that we have generated a novel and reproducible animal model for neonatal sepsis.IMPORTANCEThe development of appropriate vaccines for relies on suitable animal models for efficacy testing. However, to date, there are no small animal models of -associated neonatal sepsis. We have established a neonatal mouse model of lethal infection that is age dependent and mimics the heightened susceptibility to spp. observed in human neonates. This newly discovered mouse model represents a valuable tool to study the pathogenesis of invasive infections in the neonate and to develop novel vaccines aimed at minimizing morbidity and mortality associated with neonatal sepsis.
在低收入和中等收入国家，是新生儿败血症的主要病因。随着全球耐多药菌株比例的增加以及研发中新型抗生素的缺乏，接种疫苗以预防因感染是替代抗生素的一种策略。目前有几种疫苗正在研发中；然而，尚无可用于评估疫苗效力的与相关新生儿败血症的小动物模型。因此，我们开发并表征了一种感染的新生小鼠模型。我们发现新生C57BL/6小鼠经口接种后对血清型O1:K2高毒力菌株B5055高度易感，且小鼠对感染的易感性具有年龄和剂量依赖性。2至3日龄的小鼠在感染10⁵ - 10⁷菌落形成单位的B5055时，死亡率始终为88% - 100%。这种易感性在新生儿期逐渐降低，以至于经口给药后，该剂量的B5055在10日龄及以上的C57BL/6小鼠中无致病性。2日龄小鼠在感染后2小时即出现菌血症，同时伴随着细菌从胃肠道全身播散至脑、肝、肺和脾。然而，与未感染小鼠相比，仅肝脏和肺在门静脉周围显示炎性浸润，肺泡和肺泡腔中有嗜中性粒细胞渗出，未感染小鼠未显示病理效应。总体而言，这些结果表明我们已建立了一种用于新生儿败血症的新型且可重复的动物模型。重要性针对开发合适的疫苗依赖于用于效力测试的合适动物模型。然而，迄今为止，尚无与相关新生儿败血症的小动物模型。我们建立了一种致死性感染的新生小鼠模型，该模型具有年龄依赖性，模拟了人类新生儿中观察到的对 spp. 的易感性增加。这个新发现的小鼠模型是研究新生儿侵袭性感染发病机制以及开发旨在降低与新生儿败血症相关的发病率和死亡率的新型疫苗的宝贵工具。
