Resolution of SARS-CoV-2 infection in human lung tissues is driven by CD163+ inflammatory monocytes (RNA-Seq)

The lung-resident immune mechanisms driving resolution of SARS-CoV-2 infection in humans remain elusive due to limitations associated with human studies. Using mice co-engrafted with a human immune system and fetal lung xenograft (fLX), we mapped the immunological events defining resolution of SARS-CoV-2 infection in human lung tissues. Viral particles and RNA are rapidly cleared from fLX following a peak of viral replication. Clearance is associated with the emergence of a short-lived inflammatory monocyte (iMO) and a macrophage-like T-cell subset enriched in viral RNA. iMO exhibit an exclusive antiviral response, and the upregulation of monocyte chemoattractive signals by infected fLX underscores a link between circulating CD4+ monocyte recruitment and iMO differentiation. Consistently, mice systemically depleted for human CD4+ cells but not for CD3+ T-cells fail to robustly clear infection and display signatures of chronic infection. Our findings uncover iMO differentiation as a critical hallmark of successful resolution of SARS-CoV-2 infection in human lung tissues, and open avenues to understand the drivers of persistently active SARS-CoV-2 infection. Overall design: Bulk RNA-seq from fetal lung xenografts in BLT-L mice infected with SARS-CoV-2. Samples taken 2 and 12 days postinfection (dpi) were compared to naïve.

由于人体研究存在相关局限，驱动人类严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染消退的肺驻留免疫机制仍有待阐明。本研究采用同时植入人类免疫系统与胎儿肺异种移植物（fetal lung xenograft, fLX）的小鼠模型，绘制了人类肺组织中定义SARS-CoV-2感染消退过程的免疫事件图谱。病毒复制达到峰值后，病毒颗粒与RNA可快速从胎儿肺异种移植物中被清除。该清除过程与短命炎性单核细胞（inflammatory monocyte, iMO）以及富集病毒RNA的巨噬细胞样T细胞亚群的出现密切相关。炎性单核细胞展现出专属的抗病毒应答特征，受感染的胎儿肺异种移植物上调单核细胞趋化信号通路，这凸显了循环CD4+单核细胞招募与炎性单核细胞分化之间的潜在关联。与此一致的是，全身耗竭人类CD4+细胞而非CD3+ T细胞的小鼠无法有效清除感染，并呈现慢性感染的分子特征。本研究证实炎性单核细胞分化是人类肺组织中成功消退SARS-CoV-2感染的关键标志，同时为理解持续活跃的SARS-CoV-2感染的驱动因素开辟了研究路径。总体实验设计：对感染SARS-CoV-2的BLT-L小鼠体内的胎儿肺异种移植物开展批量RNA测序，将感染后2天与12天（dpi）的样本与未感染（naïve）样本进行对比分析。