천인수 (University of Virginia)

한빛사논문

조회459

University of Virginia

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Nature, Sep 04 2024, | https://doi.org/10.1038/s41586-024-07926-8 An aberrant immune-epithelial progenitor niche drives viral lung sequelae

Harish Narasimhan^1,2,3,16, In Su Cheon^1,2,16, Wei Qian^1,2,16, Sheng’en Shawn Hu^4,16, Tanyalak Parimon^5,6,16, Chaofan Li^1,2, Nick Goplen⁷, Yue Wu^1,2, Xiaoqin Wei^1,2, Young Min Son⁸, Elizabeth Fink^1,2, Gislane de Almeida Santos^1,2, Jinyi Tang^1,2, Changfu Yao^5,6, Lyndsey Muehling⁹, Glenda Canderan⁹, Alexandra Kadl¹⁰, Abigail Cannon^1,2, Samuel Young1,2,3, Riley Hannan¹⁰, Grace Bingham¹¹, Mohammed Arish^1,2, Arka Sen Chaudhari^1,2, Jun sub Im^1,2, Cameron L. R. Mattingly^12,13, Patcharin Pramoonjago¹⁴, Alberto Marchesvsky¹⁵, Jeffrey Sturek¹⁰, Jacob E. Kohlmeier^12,13, Yun Michael Shim¹⁰, Judith Woodfolk⁹, Chongzhi Zang⁴, Peter Chen^5,6 & Jie Sun^1,2,3

¹Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA.

²Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, USA.

³Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.

⁴Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.

⁵Women’s Guild Lung Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

⁶Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

⁷Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.

⁸Department of Systems Biotechnology, Chung-Ang University, Anseong, Korea.

⁹Division of Asthma, Allergy and Immunology, Department of Medicine, University of Virginia, Charlottesville, VA, USA.

¹⁰Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, USA.

¹¹Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.

¹²Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.

¹³Emory Center of Excellence for Influenza Research and Response, Atlanta, GA, USA.

¹⁴School of Medicine, University of Virginia, Charlottesville, VA, USA.

¹⁵Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

¹⁶These authors contributed equally: Harish Narasimhan, In Su Cheon, Wei Qian, Sheng’en Shawn Hu, Tanyalak Parimon.

Corresponding authors

Correspondence to Chongzhi Zang, Peter Chen or Jie Sun.

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 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, 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.

논문정보

형식Research article
게재일2024년 09월 (BRIC 등록일 2024-09-06)
연구진국내+국외 연구진
분야 생명과학 > 면역학

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