COVID-19 and influenza infections mediate distinct pulmonary cellular and transcriptomic changes

The study “COVID-19 and influenza infections mediate distinct pulmonary cellular and transcriptomic changes” examines the differences in lung tissue response between SARS-CoV-2 and influenza (H1N1) infections in K18-human ACE2 transgenic mice.

Key findings include:

SARS-CoV-2 Infection Leads to Persistent Lung Abnormalities: Sub-lethally infected K18-human ACE2 mice showed patchy pneumonia, histiocytic inflammation, and collagen deposition at 21 and 45 days post-infection (DPI). In contrast to influenza, SARS-CoV-2-infected mice had reduced interferon-gamma/alpha responses and failed to induce keratin 5 (Krt5), a marker of nascent pulmonary progenitor cells. This suggests SARS-CoV-2 infection does not induce the proliferation of nascent Krt5+ cells in consolidated regions, leading to incomplete repair of lung injury​​.

Prolonged COVID-19 Lung Symptoms and Fibrosis: Long COVID patients, including those with mild to moderate cases, showed prolonged lung symptoms such as fatigue, cough, and shortness of breath. Pulmonary abnormalities like fibrosis were observed in up to 11% of discharged COVID-19 patients, with minimal resolution over time. Flu infection, in contrast, showed limited scarring with the ability to recover lung capacity, involving the proliferation of multipotent basal cells expressing keratin 5​​.

Transcriptomic Analysis of Lung Tissue: In K18 mice, SARS-CoV-2 infection caused an increase in the expression of several collagen superfamily genes and other extracellular matrix protein genes at 21 DPI, indicating a chronic inflammatory response and potential mediation of fibrosis in the lungs. Additionally, increased activation of epithelial-to-mesenchymal transition pathways, hallmark inflammatory response, and interferon-gamma pathways were observed​​.

Comparison with Influenza: Flu infection induced a greater number of pro-inflammatory genes and had higher activation of interferon pathways compared to SARS-CoV-2 infection. This resulted in a more robust inflammatory response and repair mechanisms in influenza compared to COVID-19​​.

Lack of Krt5+ Cell Proliferation in SARS-CoV-2 Infection: Krt5+ cells were not found in pulmonary consolidation areas during SARS-CoV-2 infection, unlike influenza infection. This was observed in both the mouse model and human COVID-19 patients, indicating a failure of Krt5+ cells to expand during SARS-CoV-2 infection compared to influenza​​.

Sustained Collagen Deposition in SARS-CoV-2 Infected Lungs: CoV2-infected mice showed increased and sustained collagen deposition in the lungs compared to flu-infected mice, particularly at 21 DPI, suggesting persistent fibrosis in SARS-CoV-2 infection​​.

Single-cell RNA Sequencing (scRNA-seq) Analysis: scRNA-seq analyses of flu-infected mice revealed significant upregulation of interferon-induced proteins and chemokines in flu-infected lungs compared to SARS-CoV-2, further confirming down-regulation of the interferon response in COVID-19​​.

Role of Interferons in SARS-CoV-2 Infection: The study discusses the complex role of interferons in COVID-19, noting that while Type I interferons reduced viral titers and improved recovery in animal models, sustained levels are associated with increased pulmonary injury and reduced epithelial cell proliferation​​.

Increased AT2 Cell Numbers in SARS-CoV-2 Infection: The study found increased AT2 cell numbers and up-regulation of surfactant genes in SARS-CoV-2 infected mice compared to influenza, highlighting differences in the activation of molecular pathways and cell types between the two infections​​.

Overall, the study reveals significant differences in lung tissue responses between SARS-CoV-2 and influenza infections, particularly in the proliferation of progenitor cells and the subsequent repair or fibrosis of lung tissue. This contributes to our understanding of the pathogenesis of COVID-19 and the mechanisms underlying long-term respiratory complications.

Read Study: https://www.nature.com/articles/s42003-023-05626-z

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