An aberrant immune-epithelial progenitor niche drives viral lung sequelae

• 成果类型: Article
• 署名作者: Narasimhan, Harish; Cheon, In Su; Qian, Wei; Hu, Sheng'en Shawn; Parimon, Tanyalak; Li, Chaofan; Goplen, Nick; Wu, Yue; Wei, Xiaoqin; Son, Young Min; Fink, Elizabeth; Santos, Gislane de Almeida; Tang, Jinyi; Yao, Changfu; Muehling, Lyndsey; Canderan, Glenda; Kadl, Alexandra; Cannon, Abigail; Young, Samuel; Hannan, Riley; Bingham, Grace; Arish, Mohammed; Sen Chaudhari, Arka; Im, Jun Sub; Mattingly, Cameron L. R.; Pramoonjago, Patcharin; Marchesvsky, Alberto; Sturek, Jeffrey; Kohlmeier, Jacob E.; Shim, Yun Michael; Woodfolk, Judith; Zang, Chongzhi; Chen, Peter; Sun, Jie
• 署名单位: University of Virginia; University of Virginia; University of Virginia; University of Virginia; Cedars Sinai Medical Center; Cedars Sinai Medical Center; Mayo Clinic; Chung Ang University; University of Virginia; University of Virginia; University of Virginia; Emory University; University of Virginia; Cedars Sinai Medical Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5234
• DOI: 10.1038/s41586-024-07926-8
• 发表日期: 2024-10-01
• 页码: 961-+
• 关键词: pulmonary-fibrosis; infection; features

摘要

The long-term physiological consequences of respiratory viral infections, particularly in the aftermath of the COVID-19 pandemic-termed post-acute sequelae of SARS-CoV-2 (PASC)-are rapidly evolving into a major public health concern(1-3). While the cellular and molecular aetiologies of these sequelae are poorly defined, increasing evidence implicates abnormal immune responses(3-6) and/or impaired organ recovery(7-9) after infection. However, the precise mechanisms that link these processes in the context of PASC remain unclear. Here, with insights from three cohorts of patients with respiratory PASC, we established a mouse model of post-viral lung disease and identified an aberrant immune-epithelial progenitor niche unique to fibroproliferation in respiratory PASC. Using spatial transcriptomics and imaging, we found a central role for lung-resident CD8(+) T cell-macrophage interactions in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Specifically, IFN gamma and TNF derived from CD8(+) T cells stimulated local macrophages to chronically release IL-1 beta, resulting in the long-term maintenance of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFN gamma+TNF or IL-1 beta markedly improved alveolar regeneration and pulmonary function. In contrast to other approaches, which require early intervention(10), we highlight therapeutic strategies to rescue fibrotic disease after the resolution of acute disease, addressing a current unmet need in the clinical management of PASC and post-viral disease.