Epithelial Plasticity and Innate Immune Activation Promote Lung Tissue Remodeling following Respiratory Viral Infection.. Epithelial Plasticity and Innate Immune Activation Promote Lung Tissue Remodeling following Respiratory Viral Infection.

As observed in mice with genetic depletion of stem cells, epithelial plasticity is a critical component of tissue repair in response to injury; however, the physiological relevance of this process and the involved progenitor populations are not well understood. Severe respiratory viral infection and chronic lung disease share pathological features including stem cell loss in the gas-exchange regions, basal cell (BC) hyperplasia in small airways, and innate immune activation. Collectively, these processes contribute to epithelial remodeling and loss of diffusion capacity. Here, we show that small airways harbor a previously undescribed lineage of secretory cells, intralobar serous (IS) cells, that are activated to assume BC fates following influenza virus infection. Nascent BC were distinguished from pre-existing BC by high expression of IL-22Ra1 and a dependency on innate immune activation and local IL-22 production for self-renewal and colonization of injured alveoli. Resolution of virus-elicited inflammation and the associated decline in IL-22 signaling resulted in basal to serous re-differentiation in repopulated alveoli, and increased local expression of antimicrobial factors, but failed to replace normal alveolar epithelium. We define a mechanism whereby epithelial plasticity confers protection against mortality from acute respiratory viral infection but has potential to contribute to progressive lung remodeling and life-threatening declines in lung function among patients with chronic lung disease. Overall design: Single cell RNAseq was used to assess dynamic changes in gene expression and cell representation at indicated time points following influenza induced acute lung injury (naïve, 3, 5 , 7, 9 , 11, 14, 17, 21, 120, 240). Immune and Epithelial cell were enriched prior to cell capture by FACS.

正如干细胞基因敲除小鼠中所观察到的那样，上皮可塑性（epithelial plasticity）是损伤后组织修复的关键组成部分；然而，这一过程的生理学相关性以及所涉及的祖细胞群体仍未得到充分阐释。重症呼吸道病毒感染与慢性肺部疾病具有共同的病理特征，包括气体交换区域的干细胞丢失、小气道内基底细胞（basal cell, BC）增生以及先天免疫激活。上述这些过程共同介导了上皮重塑与弥散功能丧失。本研究发现，小气道内存在一类此前未被定义的分泌细胞谱系——叶内浆液细胞（intralobar serous cells, IS cells），该类细胞在流感病毒感染后可被激活并获得基底细胞（BC）命运。新生基底细胞与已存在的基底细胞可通过以下特征区分：高表达IL-22Ra1，且其自我更新以及定植损伤肺泡的过程依赖于先天免疫激活与局部IL-22的产生。病毒诱导的炎症消退以及伴随的IL-22信号通路活性下降，会使已定植的肺泡内的基底细胞向浆液细胞发生再分化，并提升局部抗菌因子的表达水平，但无法恢复正常的肺泡上皮结构。本研究阐明了一种机制：上皮可塑性可对急性呼吸道病毒感染引发的死亡起到保护作用，但同时也可能在慢性肺部疾病患者中促进进行性肺重塑，并导致危及生命的肺功能下降。实验整体设计：本研究采用单细胞RNA测序（single cell RNA-seq）技术，在流感病毒诱导的急性肺损伤后的指定时间点（未造模对照组、第3、5、7、9、11、14、17、21、120、240天）评估基因表达与细胞占比的动态变化。在细胞捕获前，通过荧光激活细胞分选术（fluorescence-activated cell sorting, FACS）富集免疫细胞与上皮细胞。