Humanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection. Kenney et al.

Summary of the study: The human immunological mechanisms defining the clinical outcome of SARS-CoV-2 infection remain elusive. This knowledge gap is mostly driven by the lack of appropriate experimental platforms recapitulating human immune responses in a controlled human lung environment. Here, we report a mouse model (i.e. HNFL mice) co-engrafted with human fetal lung xenografts (fLX) and a myeloid-enhanced human immune system to identify cellular and molecular correlates of lung protection during SARS-CoV-2 infection. Unlike mice solely engrafted with human fLX, HNFL mice are protected against infection, severe inflammation, and histopathological phenotypes. Lung tissue protection from infection and severe histopathology associate with macrophage infiltration and differentiation, and the upregulation of a macrophage-enriched signature composed of eleven specific genes mainly associated with the type I interferon signaling pathway. Our work highlights the HNFL model as a transformative platform to investigate, in controlled experimental setting, human myeloid immune mechanisms governing lung tissue protection during SARS-CoV-2 infection. This Mendeley dataset contains all of the Supplemental Items associated with this study. This includes the following: - Table S1. Related to Figure 1,4 and 6. Single-cell RNA sequencing gene-defining clusters and cluster annotation in naïve NRGL-LX and HNFL-LX, and in inoculated HNFL-LX (Excel file). - Table S2. Related to Figure 1 and 5. Proteomic analysis Matrix: Naive NRGL-LX vs. HNFL-LX, Naïve HNFL-LX vs. 2DPI HNFL0LX, Naïve NRGL-LX vs. 2DPI NRGL-LX (Excel file). - Table S3. Related to Figure 5. Phospho-proteomics analysis Matrix: Naïve HNFL-LX vs. 2DPI HNFL0LX, Naïve NRGL-LX vs. 2DPI NRGL-LX (Excel file). - Table S4. Related to Figure 5. List of differentially expressed genes and IPA scores from bulk RNA sequencing analysis of naïve and inoculated NRGL-LX (Excel file). - Table S5. Related to all figures. List of the mice and fetal donor ID used in this study (Excel file). - Movie S1. Related to Figure 2. Time-lapse (2DPI, 4DPI, 6DPI and 12DPI) 3D in vivo imaging of SARS-CoV-2 infection in NRGL mice (mp4 file).研究概述：明确新型冠状病毒（SARS-CoV-2）感染临床结局的人类免疫学机制仍不明确。这一认知空白主要源于缺乏可在可控人类肺部环境中重现人体免疫应答的合适实验平台。本研究报道了一种共移植人类胎儿肺异种移植物（fLX）与髓系增强型人类免疫系统的小鼠模型（即HNFL小鼠），用于探究新型冠状病毒感染期间肺部保护的细胞与分子关联特征。与仅移植人类胎儿肺异种移植物的小鼠不同，HNFL小鼠可抵御感染、重度炎症及组织病理学表型异常。肺部组织抵御感染与重度组织病理学损伤的保护作用，与巨噬细胞浸润、分化以及由11个主要与I型干扰素信号通路（type I interferon signaling pathway）相关的特异性基因构成的巨噬细胞富集特征基因集的上调密切相关。本研究表明，HNFL模型可作为一种变革性实验平台，在可控实验环境中探究调控新型冠状病毒感染期间肺部组织保护的人类髓系免疫机制。 本Mendeley数据集包含本研究相关的全部补充材料，具体如下： - 表S1：与图1、图4和图6相关，包含未接种NRGL-LX与HNFL-LX小鼠以及接种后HNFL-LX小鼠的单细胞RNA测序基因特征性细胞簇及细胞簇注释信息（Excel文件）。 - 表S2：与图1和图5相关，包含未接种NRGL-LX与HNFL-LX组、未接种HNFL-LX与感染后2天（2DPI）HNFL0LX组、未接种NRGL-LX与感染后2天（2DPI）NRGL-LX组的蛋白质组分析矩阵（Excel文件）。 - 表S3：与图5相关，包含未接种HNFL-LX与感染后2天（2DPI）HNFL0LX组、未接种NRGL-LX与感染后2天（2DPI）NRGL-LX组的磷酸化蛋白质组分析矩阵（Excel文件）。 - 表S4：与图5相关，包含未接种与接种后NRGL-LX小鼠批量RNA测序分析得到的差异表达基因列表及IPA评分（Excel文件）。 - 表S5：与所有图表相关，包含本研究中使用的小鼠及胎儿供体编号列表（Excel文件）。 - 影片S1：与图2相关，包含NRGL小鼠新型冠状病毒感染的延时（2DPI、4DPI、6DPI及12DPI）三维活体成像数据（MP4文件）。