2026年1月14日出版的《自然》杂志发表了索尔克生物研究所Janelle S. Ayres课题组的最新成果，他们提出了小鼠疾病耐受性和感染发病机制与年龄相关的权衡。

由于成功的疾病耐受性反应需要宿主参与与疾病本身和感染引起的病理相兼容的机制，课题组研究人员预测这种防御策略会随着年龄的增长而改变。由于疾病耐受性的差异，感染50%致死剂量（LD₅₀）病原体的动物通常表现出不同的健康和疾病轨迹，并且可以通过主题来定义耐受性机制。在多微生物脓毒症模型中，研究小组发现，尽管具有相同的LD₅₀，老年和年轻易感小鼠表现出不同的疾病症状。在年轻幸存者中，心脏Foxo1及其下游效应物Trim63 （MuRF1）可防止败血症诱导的心脏重构、多器官损伤和死亡。相反，在老年宿主中，Foxo1和Trim63是脓毒症发病和死亡的驱动因素。他们的发现对根据感染个体的年龄定制治疗具有启示意义，并表明疾病耐受基因表现出拮抗多效性。

研究人员表示，疾病耐受性是感染存活所必需的防御策略，在不杀死病原体的情况下限制生理损伤。由于随着年龄的增长而积累的结构和功能生理变化，感染可能导致的疾病的性质和病理在宿主的一生中发生变化。

附：英文原文

Title: Disease tolerance and infection pathogenesis age-related tradeoffs in mice

Author: Sanchez, Karina K., McCarville, Justin L., Stengel, Sarah J., Snyder, Jessica M., Williams, April E., Ayres, Janelle S.

Issue&Volume: 2026-01-14

Abstract: Disease tolerance is a defence strategy essential for survival of infections, limiting physiological damage without killing the pathogen1,2. The disease course and pathology an infection may cause can change over the lifespan of a host due to the structural and functional physiological changes that accumulate with age. Because successful disease tolerance responses require the host to engage mechanisms that are compatible with the disease course and pathology caused by an infection, we predicted that this defence strategy would change with age. Animals infected with a 50% lethal dose  (LD50) of a pathogen often show distinct health and sickness trajectories due to differences in disease tolerance1,3 and can be used to define tolerance mechanisms. Here, using a polymicrobial sepsis model, we found that, despite having the same LD50, aged and young susceptible mice showed distinct disease courses. In young survivors, cardiac Foxo1 and its downstream effector Trim63 (MuRF1) protected from sepsis-induced cardiac remodelling, multi-organ injury and mortality. Conversely, in aged hosts, Foxo1 and Trim63 acted as drivers of sepsis pathogenesis and death. Our findings have implications for the tailoring of therapy to the age of an infected individual and indicate that disease tolerance genes show antagonistic pleiotropy.

DOI: 10.1038/s41586-025-09923-x

Source: https://www.nature.com/articles/s41586-025-09923-x