NatureSep 4, 2024

A faulty immune and lung cell environment may cause lasting lung problems after viral infection

Updated Dec 30, 2025

Abstract

A unique immune response may contribute to long-term lung damage after respiratory viral infections.

An abnormal immune-epithelial niche linked to lung fibrosis was identified in patients with respiratory post-acute sequelae of SARS-CoV-2 (PASC).
Interactions between lung-resident CD8 T cells and macrophages may hinder the body's ability to regenerate lung tissue after viral pneumonia.
Cytokines like IFNγ and TNF from CD8 T cells could lead to chronic IL-1β release from macrophages, maintaining abnormal lung cells and fibrosis.
Therapeutic targeting of IFNγ, TNF, or IL-1β may improve lung function and tissue repair after acute respiratory infections.
Strategies to treat fibrotic disease after the acute phase may address a significant gap in managing PASC.

Simplified

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. While the cellular and molecular aetiologies of these sequelae are poorly defined, increasing evidence implicates abnormal immune responsesand/or impaired organ recoveryafter 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 CD8T cell-macrophage interactions in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Specifically, IFNγ and TNF derived from CD8T 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 intervention, 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. 1-3 3-6 7-9 + + 10

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Funding

Competing interests

Competing interests J. Sun receives support for research unrelated to this project from Icosavax. J.W. receives support for research unrelated to this project from Regeneron.

PubMed

A faulty immune and lung cell environment may cause lasting lung problems after viral infection

Abstract

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Funding

Competing interests

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Abstract

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Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

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