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Updated: May 28, 2026

Modeling Dysplastic and Functional Lung Alveolar Repair after Influenza Infection
Published on: September 19, 2025
Potential role for alternatively activated macrophages in the secondary bacterial infection during recovery from
Wilbur H Chen1, Franklin R Toapanta, Kari Ann Shirey
1Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA. wchen@medicine.umaryland.edu
Purpose:
Secondary bacterial infections are a common complication of influenza. Innate immune host defenses appear to be impaired following influenza, leading to susceptibility to subsequent bacterial infections. Alternatively activated macrophages (AAM) in the lungs may play a critical role in eliciting the hypersusceptibility to secondary bacterial pneumonia.
Methods:
C57BL6 mice were challenged with sublethal doses of the mouse-adapted A/PR/8/34 (PR8) influenza virus or saline and allowed to recover. At complete recovery (day 14), mice were re-challenged with sublethal doses of Streptococcus pneumoniae serotype 3 (Sp3).
Results:
PR8-recovered mice developed a rapidly fatal pulmonary infection to a 100-fold sublethal pneumococcal challenge, whereas PR8-naive mice demonstrated no mortality or illness. The cytokines which induce AAM (IL-4 and IL-13) and the expression of genes associated with AAM (Arginase-1, FIZZ1, and YM1) were elevated after PR8 infection. Flow cytometry suggests that alveolar macrophages demonstrate the AAM-phenotype, as indicated by MGL-1 and MHCII expression, in response to PR8 infection. Recovery from PR8 was associated with blunted cytokine responses to TLR ligands.
Conclusions:
The mechanisms of immune regulation during recovery from influenza are being elucidated. We provide evidence that pulmonary AAM are induced during influenza infection and may contribute to the elicitation of hypersusceptibility to a secondary bacterial infection.
Insights
Influenza infection impairs immune defenses, making mice susceptible to secondary bacterial pneumonia. Pulmonary alternatively activated macrophages (AAM) induced by influenza may drive this increased susceptibility.
Area of Science:
- Immunology
- Infectious Diseases
- Pulmonary Medicine
Background:
- Secondary bacterial infections frequently complicate influenza virus infections.
- Impaired innate immune defenses post-influenza contribute to heightened susceptibility to bacterial pathogens.
- Pulmonary alternatively activated macrophages (AAM) are implicated in the hypersusceptibility to secondary bacterial pneumonia.
Purpose of the Study:
- To investigate the role of pulmonary alternatively activated macrophages (AAM) in the increased susceptibility to secondary bacterial pneumonia following influenza infection.
- To elucidate the mechanisms of immune regulation during recovery from influenza.
Main Methods:
- C57BL6 mice were infected with sublethal doses of influenza A virus (PR8) or saline.
- Following recovery, mice were re-challenged with Streptococcus pneumoniae.
- Gene expression, flow cytometry, and cytokine responses were analyzed.
Main Results:
- Mice recovered from influenza (PR8) exhibited a 100-fold increased susceptibility to a lethal Streptococcus pneumoniae challenge compared to naive mice.
- Pulmonary AAM markers (Arginase-1, FIZZ1, YM1) and associated cytokines (IL-4, IL-13) were upregulated post-influenza.
- Alveolar macrophages displayed AAM phenotype markers (MGL-1, MHCII) after PR8 infection.
- Influenza recovery was linked to blunted cytokine responses to TLR ligands.
Conclusions:
- Pulmonary alternatively activated macrophages (AAM) are induced during influenza infection.
- These AAM may play a critical role in mediating hypersusceptibility to secondary bacterial pneumonia after influenza.
- Further research into influenza-induced immune dysregulation is warranted.
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