Abstract
Infectious disease and sepsis represent a serious problem for all, but especially in early life. Much of the increase in morbidity and mortality due to infection in early life is presumed to relate to fundamental differences between neonatal and adult immunity. Mechanistic insight into the way newborns’ immune systems handle infectious threats is lacking; as a result, there has only been limited success in providing effective immunomodulatory interventions to reduce infectious mortality. Given the complexity of the host-pathogen interactions, neonatal mouse models can offer potential avenues providing valuable data. However, the small size of neonatal mice hampers the ability to collect biological samples without sacrificing the animals. Further, the lack of a standardized metric to quantify newborn mouse health increases reliance on correlative biomarkers without a known relationship to ‘clinical’ outcome. To address this bottleneck, we developed a system that allows assessment of neonatal mouse health in a readily standardized and quantifiable manner. The resulting health scores require no special equipment or sample collection and can be assigned in less than 20 seconds. Importantly, the health scores are highly predictive of survival. A classifier built on our health score revealed a positive relationship between reduced bacterial load and survival, demonstrating how this scoring system can be used to bridge the gap between assumed relevance of biomarkers and the clinical outcome of interest. Adoption of this scoring system will not only provide a robust metric to assess health of newborn mice but will also allow for objective, prospective studies of infectious disease and possible interventions in early life.
Highlights
As 24 hours post challenge (HPC) was as far into disease progression as one could wait to sacrifice mice without incurring heavy survivor bias (Fig 1B), this timepoint became the time of sacrifice for the alternative cohort of mice assessed for bacterial load
We present a system of health scores for neonatal mice which were used to confidently predict mortality 24 HPC in an established model of neonatal sepsis [19]
The significance of this is twofold: 1) the classifier enables investigators to include “clinical” outcome as a covariate of interest when all animals are sacrificed, and 2) the scoring system can represent a new standard in recording and reporting neonatal mouse health which has implications beyond this specific model
Summary
Predictive health scores in neonatal mouse model of sepsis data collection and analysis, decision to publish, or preparation of the manuscript. The addition of our health scores to neonatal mouse experiments provides: (a) an improved ability to track disease progression which can inform time of sacrifice for sample collection and (b) a quantitative method to prospectively differentiate survivors from non-survivors. It was critical to be able to distinguish survivors and non-survivors prior to sacrifice and no Predictive health scores in neonatal mouse model of sepsis later than 24 HPC.
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