An aberrant immune–epithelial progenitor niche drives viral lung sequelae

Harish Narasimhan, In Su Cheon, Wei Qian, Sheng’en Shawn Hu, Tanyalak Parimon, Chaofan Li, Nick Goplen, Yue Wu, Xiaoqin Wei, Young Min Son, Elizabeth Fink, Gislane de Almeida Santos, Jinyi Tang, Changfu Yao, Lyndsey Muehling, Glenda Canderan, Alexandra Kadl, Abigail Cannon, Samuel Young, Riley Hannan, Grace Bingham, Mohammed Arish, Arka Sen Chaudhari, Jun sub Im, Cameron L. R. Mattingly, Patcharin Pramoonjago, Alberto Marchesvsky, Jeffrey Sturek, Jacob E. Kohlmeier, Yun Michael Shim, Judith Woodfolk, Chongzhi Zang (), Peter Chen () and Jie Sun ()
Additional contact information
Harish Narasimhan: University of Virginia
In Su Cheon: University of Virginia
Wei Qian: University of Virginia
Sheng’en Shawn Hu: University of Virginia School of Medicine
Tanyalak Parimon: Cedars-Sinai Medical Center
Chaofan Li: University of Virginia
Nick Goplen: Mayo Clinic
Yue Wu: University of Virginia
Xiaoqin Wei: University of Virginia
Young Min Son: Chung-Ang University
Elizabeth Fink: University of Virginia
Gislane de Almeida Santos: University of Virginia
Jinyi Tang: University of Virginia
Changfu Yao: Cedars-Sinai Medical Center
Lyndsey Muehling: University of Virginia
Glenda Canderan: University of Virginia
Alexandra Kadl: University of Virginia
Abigail Cannon: University of Virginia
Samuel Young: University of Virginia
Riley Hannan: University of Virginia
Grace Bingham: University of Virginia
Mohammed Arish: University of Virginia
Arka Sen Chaudhari: University of Virginia
Jun sub Im: University of Virginia
Cameron L. R. Mattingly: Emory University School of Medicine
Patcharin Pramoonjago: University of Virginia
Alberto Marchesvsky: Cedars-Sinai Medical Center
Jeffrey Sturek: University of Virginia
Jacob E. Kohlmeier: Emory University School of Medicine
Yun Michael Shim: University of Virginia
Judith Woodfolk: University of Virginia
Chongzhi Zang: University of Virginia School of Medicine
Peter Chen: Cedars-Sinai Medical Center
Jie Sun: University of Virginia

Nature, 2024, vol. 634, issue 8035, 961-969

Abstract: Abstract 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 concern1–3. While the cellular and molecular aetiologies of these sequelae are poorly defined, increasing evidence implicates abnormal immune responses3–6 and/or impaired organ recovery7–9 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, IFNγ and TNF derived from CD8+ T cells stimulated local macrophages to chronically release IL-1β, resulting in the long-term maintenance of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFNγ + TNF or IL-1β markedly improved alveolar regeneration and pulmonary function. In contrast to other approaches, which require early intervention10, 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.

Date: 2024
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DOI: 10.1038/s41586-024-07926-8

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