Chen Grischa Y, Thorup Natalia R, Miller Abigail J, Li Yao-Cheng, Ayres Janelle S
Molecular and Systems Physiology Lab, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.
bioRxiv. 2023 Feb 26:2023.01.22.525099. doi: 10.1101/2023.01.22.525099.
Animals have evolved two defense strategies to survive infections. Antagonistic strategies include mechanisms of immune resistance that operate to sense and kill invading pathogens. Cooperative or physiological defenses mediate host adaptation to the infected state, limiting physiological damage and disease, without killing the pathogen, and have been shown to cause asymptomatic carriage and transmission of lethal pathogens. Here we demonstrate that physiological defenses cooperate with the adaptive immune response to generate long-term asymptomatic carriage of the lethal enteric murine pathogen, Citrobacter rodentium. Asymptomatic carriage of genetically virulent C. rodentium provided immune resistance against subsequent infections. Host immune protection was dependent on systemic antibody responses and pathogen virulence behavior, rather than the recognition of specific virulent factor antigens. Finally, we demonstrate that an avirulent strain of C. rodentium in the field has background mutations in two genes that are important for LPS structure. Our work reveals novel insight into how asymptomatic infections can arise mechanistically with immune resistance, mediating exclusion of phenotypically virulent enteric pathogen to promote asymptomatic carriage.
动物已经进化出两种防御策略来在感染中生存。对抗性策略包括免疫抵抗机制，其作用是感知并杀死入侵的病原体。协同或生理性防御介导宿主适应感染状态，限制生理损伤和疾病，而不杀死病原体，并且已被证明会导致致死性病原体的无症状携带和传播。在此，我们证明生理性防御与适应性免疫反应协同作用，以产生致死性肠道鼠病原体——鼠柠檬酸杆菌的长期无症状携带。基因毒性鼠柠檬酸杆菌的无症状携带提供了针对后续感染的免疫抵抗力。宿主免疫保护依赖于全身性抗体反应和病原体毒力行为，而非对特定毒力因子抗原的识别。最后，我们证明野外一株无毒力的鼠柠檬酸杆菌在两个对脂多糖结构很重要的基因中存在背景突变。我们的工作揭示了关于无症状感染如何通过免疫抵抗机制产生、介导排除表型毒性肠道病原体以促进无症状携带的新见解。
