Intergenerational inheritance of trained immunity and heterologous resistance to infections (ATAC-seq)

Intergenerational inheritance (Inter-I) of phenotypic characteristics has been demonstrated in plants and invertebrates, with epigenetic modifications playing a role in the inheritance of a variety of features such as appearance1, adaptation to stress, or resistance to infections. Here we provide evidence of Inter-I of transcriptional and epigenetic signatures of trained immunity to the progeny of mice that survived a sublethal systemic Candida albicans infection. Intergenerational trained mice (F1) presented with significant cellular, developmental, transcriptional, and epigenetic changes within the bone marrow resident myeloid effector and progenitor cell compartment. These alterations led to an enhanced responsiveness to in vivo endotoxin challenge and Escherichia coli infection, providing the offspring with protection against heterologous infections. These results argue for the contribution of Lamarckian evolutionary processes to protect against infections in vertebrates. Overall design: Male mice were infected with subletal dose of C. albicans. One month after clearance of the infection, 'resting' (mock-infected with PBS, F0R) and the 'trained' (C. albicans-infected and recovered, F0T) mice were mated with healthy non-infected females. FACS-enriched granulocyte macrophage progenitors (GMP) from the bone marrow of the offspring (F1T and F1R, respecively) were subjected to chromatin accessability analysis by ATAC-seq.

表型特征的跨代遗传（Inter-I）已在植物与无脊椎动物中得到证实，表观遗传修饰在多种性状的遗传过程中发挥作用，包括外观1、应激适应性以及抗感染能力。本研究证实了经亚致死系统性白色念珠菌（Candida albicans）感染后存活的小鼠子代，其训练免疫的转录与表观遗传特征存在跨代遗传现象。跨代训练免疫小鼠（F1）的骨髓驻留髓系效应细胞与祖细胞区室中，出现了显著的细胞、发育、转录及表观遗传层面的改变。这些改变使其对体内内毒素攻击与大肠杆菌（Escherichia coli）感染的应答能力增强，从而为子代提供了对抗异源感染的保护作用。上述结果表明，拉马克式进化过程有助于脊椎动物抵御感染。

实验设计：将雄性小鼠以亚致死剂量感染白色念珠菌。在感染清除一个月后，分别将“静息组”（经PBS模拟感染，F0R）与“训练组”（经白色念珠菌感染并康复，F0T）的雄性小鼠与健康未感染雌性小鼠交配。分别从子代（F1T与F1R）的骨髓中获取经流式细胞术（FACS）分选富集的粒-巨噬细胞祖细胞（GMP），并通过转座酶可及性测序（ATAC-seq）进行染色质可及性分析。