A new murine gram-negative sepsis model with standard care satisfies Sepsis-3 and reproduces clinical pathology.

backgroundSepsis accounts for approximately a third of global mortality, and significant morbidity and economic burden. Whilst the current Sepsis-3 definition has augmented patient identification, supportive care and survival, a lack of clinically relevant animal models has limited our understanding of sepsis disease dynamics over time. Specifically, key knowledge gaps in chronic pathology underpinning the mechanisms leading to organ dysfunction and mortality rates of sepsis survivors have hindered the development of effective therapeutics. Therefore, we developed a new mouse model of abdominal gram-negative sepsis that adheres to Sepsis-3 definitions and expert-led consensus criteria for preclinical sepsis models.

resultsWe tested multiple live strains of Escherichia coli with only clinical isolates causing lethality. Subsequent standard care including broad-spectrum antibiotics and fluid resuscitation reduced the mortality rate to approximately 24 ± 9.3% (SEM), corroborating clinical observations. Early sepsis disease 12 h post-infection was characterized by cytokine storm, with concentrations of IFN-γ, CCL2, IL-6, IL-17A, IL-1α, IL-10 and M-CSF significantly elevated in multiple tissues up to 7 days post-infection when mice had recovered from objective clinical measures of disease. Furthermore, we observed histological evidence of organ dysfunction in the liver, spleen and kidney at 12 h to 3 days post-infection, validating concurrently increased serum markers of organ damage in our model. Additionally, infected mice treated with standard care exhibited persistent haematological dysfunction, as evidenced by anaemia, thrombocytosis and neutrophilia, at recovery from organ dysfunction 7 days post-infection, features similarly observed in clinical sepsis patients.

conclusionsOur new abdominal gram-negative murine sepsis model recapitulates key disease outcomes observed in sepsis patients and allows the study of dysfunctional homeostasis in surviving animals. This model can be utilized to identify and test new therapeutics for abdominal gram-negative sepsis or investigate novel mechanisms of immune dysfunction in sepsis survivors. Modifications to our murine model by utilizing alternate clinical pathogens, routes of infection, and mixed-sex, outbred or aged mice are necessary to recapitulate clinical sepsis heterogeneity and address the inherent limitations of preclinical models. Here, our methodology to establish a model with clinical isolates, satisfaction of Sepsis-3 definitions and preclinical sepsis guidelines provides a framework for the development of future models.