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<p>The Omicron sub-lineages of SARS-CoV-2 have caused a significant acute disease burden on human health and strained public health and healthcare services, while eliciting chronic disease outcomes as well. As such, the development of animal models that provoke acute and chronic disease phenotypes is essential for understanding disease mechanisms and for the development of interventional countermeasures. To address this, we infected aged BALB/c mice with mouse-adapted SARS-CoV-2 Omicron BA.1 virus (BA.1 MA), which resulted in significant weight loss, reduced lung function, and anosmia during the acute disease phase. We observed viral RNA in sustentacular cells in the upper nasal airways, club cells in lower bronchiolar airways, and alveolar type 2 epithelial cells (AT2 cells) in the alveolar parenchyma. Four months post-infection, post-acute lung pathology was observed that was characteristic of an organized pneumonia with inflammatory infiltrates, tertiary lymphoid structures, and fibrotic lesions. Highly multiplexed immunostaining and spatial transcriptomics indicate the molecular signature of the post-acute fibrotic lesion is consistent with idiopathic fibrosis. Together, this system enables the further study of acute and chronic fibrotic lung disease mechanisms and therapeutic approaches to minimize the symptoms of life-threatening respiratory disease.</p>

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Persistent lung inflammation and fibrosis after mouse-adapted Omicron BA.1 infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • John M. Powers,
  • Sarah R. Leist,
  • Lily E. Adams,
  • Anne M. Cawley,
  • Rodney C. Gilmore,
  • Nicholas J. Catanzaro,
  • Hiroaki Murano,
  • Hong Dang,
  • Lisa C. Morton,
  • Seth J. Zost,
  • Naveenchandra Suryadevara,
  • Albert Wielgus,
  • Boyd L. Yount,
  • Anfal Abdelgadir,
  • Abbey L. Perry,
  • Fernando R. Moreira,
  • Michael L. Mallory,
  • Caitlin E. Edwards,
  • Jennifer E. Munt,
  • Trevor D. Scobey,
  • Rita M. Meganck,
  • Longping V. Tse,
  • Kendra L. Gully,
  • Gabriela De la Cruz,
  • Alexis B. Bailey,
  • Jesica Swanstrom,
  • Mark R. Zweigart,
  • James E. Crowe Jr,
  • Stephen A. Schworer,
  • Stephanie A. Montgomery,
  • Wanda K. O’Neal,
  • Richard C. Boucher,
  • Timothy P. Sheahan,
  • Alessandra Livraghi-Butrico,
  • Jack R. Harkema,
  • Kenichi Okuda,
  • Ralph S. Baric

摘要

The Omicron sub-lineages of SARS-CoV-2 have caused a significant acute disease burden on human health and strained public health and healthcare services, while eliciting chronic disease outcomes as well. As such, the development of animal models that provoke acute and chronic disease phenotypes is essential for understanding disease mechanisms and for the development of interventional countermeasures. To address this, we infected aged BALB/c mice with mouse-adapted SARS-CoV-2 Omicron BA.1 virus (BA.1 MA), which resulted in significant weight loss, reduced lung function, and anosmia during the acute disease phase. We observed viral RNA in sustentacular cells in the upper nasal airways, club cells in lower bronchiolar airways, and alveolar type 2 epithelial cells (AT2 cells) in the alveolar parenchyma. Four months post-infection, post-acute lung pathology was observed that was characteristic of an organized pneumonia with inflammatory infiltrates, tertiary lymphoid structures, and fibrotic lesions. Highly multiplexed immunostaining and spatial transcriptomics indicate the molecular signature of the post-acute fibrotic lesion is consistent with idiopathic fibrosis. Together, this system enables the further study of acute and chronic fibrotic lung disease mechanisms and therapeutic approaches to minimize the symptoms of life-threatening respiratory disease.