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Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection.

Schneider C, Nobs SP, Heer AK, Kurrer M, Klinke G, van Rooijen N, Vogel J, Kopf M - PLoS Pathog. (2014)

Bottom Line: Alveolar macrophages (AM) are critical for defense against bacterial and fungal infections.However, a definitive role of AM in viral infections remains unclear.Taken together, our results suggest a superior role of AM compared to CD103+ DCs in protection from acute influenza and vaccinia virus infection-induced morbidity and mortality.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.

ABSTRACT
Alveolar macrophages (AM) are critical for defense against bacterial and fungal infections. However, a definitive role of AM in viral infections remains unclear. We here report that AM play a key role in survival to influenza and vaccinia virus infection by maintaining lung function and thereby protecting from asphyxiation. Absence of AM in GM-CSF-deficient (Csf2-/-) mice or selective AM depletion in wild-type mice resulted in impaired gas exchange and fatal hypoxia associated with severe morbidity to influenza virus infection, while viral clearance was affected moderately. Virus-induced morbidity was far more severe in Csf2-/- mice lacking AM, as compared to Batf3-deficient mice lacking CD8α+ and CD103+ DCs. Csf2-/- mice showed intact anti-viral CD8+ T cell responses despite slightly impaired CD103+ DC development. Importantly, selective reconstitution of AM development in Csf2rb-/- mice by neonatal transfer of wild-type AM progenitors prevented severe morbidity and mortality, demonstrating that absence of AM alone is responsible for disease severity in mice lacking GM-CSF or its receptor. In addition, CD11c-Cre/Ppargfl/fl mice with a defect in AM but normal adaptive immunity showed increased morbidity and lung failure to influenza virus. Taken together, our results suggest a superior role of AM compared to CD103+ DCs in protection from acute influenza and vaccinia virus infection-induced morbidity and mortality.

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Defective gas exchange and respiratory failure following influenza virus infection in Csf2−/− mice lacking AM.WT and Csf2−/− mice were infected i.t. with 50 pfu PR8 influenza virus. (A) Panels show H&E-stained histological lung sections of day 10-infected WT and Csf2−/− mice. The concentration of total protein (B) and cholesterol (C) in the BAL was determined at the indicated time points after infection. (D) Percentages of dead cells (eFluor780+) and debris (eFluor780−CD45−) in the BAL were determined by flow cytometry at d6 and d10. Bar graphs show the total BAL event number (E) and numbers of eFluor780+ or eFluor780−CD45− events (F). Shown is the mean ± SD of 4–5 mice per group. Arterial blood oxygen saturation (G) and O2 partial pressure (H) was measured in infected animals at day 9. Symbols represent values of individual mice and the mean is shown.
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ppat-1004053-g004: Defective gas exchange and respiratory failure following influenza virus infection in Csf2−/− mice lacking AM.WT and Csf2−/− mice were infected i.t. with 50 pfu PR8 influenza virus. (A) Panels show H&E-stained histological lung sections of day 10-infected WT and Csf2−/− mice. The concentration of total protein (B) and cholesterol (C) in the BAL was determined at the indicated time points after infection. (D) Percentages of dead cells (eFluor780+) and debris (eFluor780−CD45−) in the BAL were determined by flow cytometry at d6 and d10. Bar graphs show the total BAL event number (E) and numbers of eFluor780+ or eFluor780−CD45− events (F). Shown is the mean ± SD of 4–5 mice per group. Arterial blood oxygen saturation (G) and O2 partial pressure (H) was measured in infected animals at day 9. Symbols represent values of individual mice and the mean is shown.

Mentions: As shown above, absence of AM in mice lacking GM-CSF results in accumulation of surfactant material and dead cells under homeostatic conditions. Interestingly, influenza virus infection strikingly aggravated pulmonary alveolar proteinosis in Csf2−/− mice indicated by an obstruction of alveoli with aggregates of eosinophilic material (Figure 4A), increased total protein concentration (Figure 4B) and accumulation of surfactant material in the BAL fluid at days 6 and 10 p.i. (Figure 4C). Moreover, the BAL of Csf2−/− mice was highly enriched in dead cells and cellular debris indicating impaired clearance of apoptotic cells (Figure 4D–F). Accordingly, respiratory function as measured by arterial oxygen levels was critically impaired at the time when Csf2−/− mice succumb to infection (Figure 4 G, H). These results suggest that AM prevent influenza induced morbidity by maintenance of lung function through removal of dead cells and surfactant material.


Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection.

Schneider C, Nobs SP, Heer AK, Kurrer M, Klinke G, van Rooijen N, Vogel J, Kopf M - PLoS Pathog. (2014)

Defective gas exchange and respiratory failure following influenza virus infection in Csf2−/− mice lacking AM.WT and Csf2−/− mice were infected i.t. with 50 pfu PR8 influenza virus. (A) Panels show H&E-stained histological lung sections of day 10-infected WT and Csf2−/− mice. The concentration of total protein (B) and cholesterol (C) in the BAL was determined at the indicated time points after infection. (D) Percentages of dead cells (eFluor780+) and debris (eFluor780−CD45−) in the BAL were determined by flow cytometry at d6 and d10. Bar graphs show the total BAL event number (E) and numbers of eFluor780+ or eFluor780−CD45− events (F). Shown is the mean ± SD of 4–5 mice per group. Arterial blood oxygen saturation (G) and O2 partial pressure (H) was measured in infected animals at day 9. Symbols represent values of individual mice and the mean is shown.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3974877&req=5

ppat-1004053-g004: Defective gas exchange and respiratory failure following influenza virus infection in Csf2−/− mice lacking AM.WT and Csf2−/− mice were infected i.t. with 50 pfu PR8 influenza virus. (A) Panels show H&E-stained histological lung sections of day 10-infected WT and Csf2−/− mice. The concentration of total protein (B) and cholesterol (C) in the BAL was determined at the indicated time points after infection. (D) Percentages of dead cells (eFluor780+) and debris (eFluor780−CD45−) in the BAL were determined by flow cytometry at d6 and d10. Bar graphs show the total BAL event number (E) and numbers of eFluor780+ or eFluor780−CD45− events (F). Shown is the mean ± SD of 4–5 mice per group. Arterial blood oxygen saturation (G) and O2 partial pressure (H) was measured in infected animals at day 9. Symbols represent values of individual mice and the mean is shown.
Mentions: As shown above, absence of AM in mice lacking GM-CSF results in accumulation of surfactant material and dead cells under homeostatic conditions. Interestingly, influenza virus infection strikingly aggravated pulmonary alveolar proteinosis in Csf2−/− mice indicated by an obstruction of alveoli with aggregates of eosinophilic material (Figure 4A), increased total protein concentration (Figure 4B) and accumulation of surfactant material in the BAL fluid at days 6 and 10 p.i. (Figure 4C). Moreover, the BAL of Csf2−/− mice was highly enriched in dead cells and cellular debris indicating impaired clearance of apoptotic cells (Figure 4D–F). Accordingly, respiratory function as measured by arterial oxygen levels was critically impaired at the time when Csf2−/− mice succumb to infection (Figure 4 G, H). These results suggest that AM prevent influenza induced morbidity by maintenance of lung function through removal of dead cells and surfactant material.

Bottom Line: Alveolar macrophages (AM) are critical for defense against bacterial and fungal infections.However, a definitive role of AM in viral infections remains unclear.Taken together, our results suggest a superior role of AM compared to CD103+ DCs in protection from acute influenza and vaccinia virus infection-induced morbidity and mortality.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.

ABSTRACT
Alveolar macrophages (AM) are critical for defense against bacterial and fungal infections. However, a definitive role of AM in viral infections remains unclear. We here report that AM play a key role in survival to influenza and vaccinia virus infection by maintaining lung function and thereby protecting from asphyxiation. Absence of AM in GM-CSF-deficient (Csf2-/-) mice or selective AM depletion in wild-type mice resulted in impaired gas exchange and fatal hypoxia associated with severe morbidity to influenza virus infection, while viral clearance was affected moderately. Virus-induced morbidity was far more severe in Csf2-/- mice lacking AM, as compared to Batf3-deficient mice lacking CD8α+ and CD103+ DCs. Csf2-/- mice showed intact anti-viral CD8+ T cell responses despite slightly impaired CD103+ DC development. Importantly, selective reconstitution of AM development in Csf2rb-/- mice by neonatal transfer of wild-type AM progenitors prevented severe morbidity and mortality, demonstrating that absence of AM alone is responsible for disease severity in mice lacking GM-CSF or its receptor. In addition, CD11c-Cre/Ppargfl/fl mice with a defect in AM but normal adaptive immunity showed increased morbidity and lung failure to influenza virus. Taken together, our results suggest a superior role of AM compared to CD103+ DCs in protection from acute influenza and vaccinia virus infection-induced morbidity and mortality.

Show MeSH
Related in: MedlinePlus