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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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CD11c-Cre/Ppargfl/fl mice have a reduced resistance to influenza virus infection despite an intact antiviral adaptive response.Ppargfl/fl and CD11c-Cre/Ppargfl/fl mice were infected i.t. with 250 pfu PR8 influenza virus. Loss of body weight (A), temperature (B) and survival (C) was monitored. Values indicate mean ± SEM of 9–10 mice per group. (D–K) For the characterization of the anti-viral immune response, Ppargfl/fl and CD11cCre/Ppargfl/fl mice were infected i.t. with 50 pfu PR8 influenza virus. Symbols represent values of individual mice and the mean is indicated. (D) The virus titers in the lung were determined at d3, d5 and d9 after infection. (E) Total numbers of influenza NP34-specific CD8+ T cells in the BAL were analyzed at d10 post-infection. (F) Influenza HA-specific IgG2c antibody concentrations in the BAL at d13 post-infection were determined by ELISA. Values indicate mean ± SEM of 4–5 mice per group. (G) Total protein in the BAL was measured at indicated time points. (H) Cytospins of BAL isolated from infected mice at d9 were stained with Oil Red O. Micrographs were taken at 63× magnification. Representative pictures of 2 individual mice are shown. (I) Panels show lung sections of day 9-infected mice stained using the Verhoeff-Van Gieson protocol. (J and K) Lung function was measured in naïve and day 9-infected animals. Arterial blood oxygen partial pressure (J) and O2 saturation (K) are shown.
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ppat-1004053-g007: CD11c-Cre/Ppargfl/fl mice have a reduced resistance to influenza virus infection despite an intact antiviral adaptive response.Ppargfl/fl and CD11c-Cre/Ppargfl/fl mice were infected i.t. with 250 pfu PR8 influenza virus. Loss of body weight (A), temperature (B) and survival (C) was monitored. Values indicate mean ± SEM of 9–10 mice per group. (D–K) For the characterization of the anti-viral immune response, Ppargfl/fl and CD11cCre/Ppargfl/fl mice were infected i.t. with 50 pfu PR8 influenza virus. Symbols represent values of individual mice and the mean is indicated. (D) The virus titers in the lung were determined at d3, d5 and d9 after infection. (E) Total numbers of influenza NP34-specific CD8+ T cells in the BAL were analyzed at d10 post-infection. (F) Influenza HA-specific IgG2c antibody concentrations in the BAL at d13 post-infection were determined by ELISA. Values indicate mean ± SEM of 4–5 mice per group. (G) Total protein in the BAL was measured at indicated time points. (H) Cytospins of BAL isolated from infected mice at d9 were stained with Oil Red O. Micrographs were taken at 63× magnification. Representative pictures of 2 individual mice are shown. (I) Panels show lung sections of day 9-infected mice stained using the Verhoeff-Van Gieson protocol. (J and K) Lung function was measured in naïve and day 9-infected animals. Arterial blood oxygen partial pressure (J) and O2 saturation (K) are shown.

Mentions: Mice lacking Pparg specifically in macrophages (LysM-Cre/Ppargfl/fl) develop pulmonary alveolar proteinosis [35]. Moreover, using CD11c-Cre/Ppargfl/fl mice that lack Pparg in AM and DCs, we recently found that development of AM is arrested in an immature state with a defect in surfactant catabolism and lipid metabolism while development of DC subsets remained unaffected (data not shown). To determine whether absence of functional AM affects resistance of CD11c-Cre/Ppargfl/fl mice to respiratory viral infection, we infected WT and CD11c-Cre/Ppargfl/fl mice with influenza virus PR8. Compared to WT, CD11c-Cre/Ppargfl/fl mice showed an earlier onset and more pronounced loss of body weight and body temperature (Figure 7A, B) associated with increased lethality (Figure 7C), although lung virus titers were insignificantly elevated (Figure 7D). Besides a slightly increased number of neutrophils, recruitment of inflammatory cells to the lung was in general normal in CD11c-Cre/Ppargfl/fl mice (Figure S6). Moreover, we found similar frequencies and total numbers of anti-viral CD8+ T cells as well as IFNγ-producing CD4+ and CD8+ T cells (Figure 7E and Figure S6) indicating that DC-mediated T cell priming and effector responses were unaffected in CD11c-Cre/Ppargfl/fl mice. Likewise, levels of anti-influenza HA-specific antibody levels (i.e. IgG2c, IgA and IgG1) were comparable in BAL and serum of CD11c-Cre/Ppargfl/fl and WT mice (Figure 7F and Figure S6). Together these results indicate that innate and adaptive anti-viral immune responses were largely intact in CD11c-Cre/Ppargfl/fl mice.


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)

CD11c-Cre/Ppargfl/fl mice have a reduced resistance to influenza virus infection despite an intact antiviral adaptive response.Ppargfl/fl and CD11c-Cre/Ppargfl/fl mice were infected i.t. with 250 pfu PR8 influenza virus. Loss of body weight (A), temperature (B) and survival (C) was monitored. Values indicate mean ± SEM of 9–10 mice per group. (D–K) For the characterization of the anti-viral immune response, Ppargfl/fl and CD11cCre/Ppargfl/fl mice were infected i.t. with 50 pfu PR8 influenza virus. Symbols represent values of individual mice and the mean is indicated. (D) The virus titers in the lung were determined at d3, d5 and d9 after infection. (E) Total numbers of influenza NP34-specific CD8+ T cells in the BAL were analyzed at d10 post-infection. (F) Influenza HA-specific IgG2c antibody concentrations in the BAL at d13 post-infection were determined by ELISA. Values indicate mean ± SEM of 4–5 mice per group. (G) Total protein in the BAL was measured at indicated time points. (H) Cytospins of BAL isolated from infected mice at d9 were stained with Oil Red O. Micrographs were taken at 63× magnification. Representative pictures of 2 individual mice are shown. (I) Panels show lung sections of day 9-infected mice stained using the Verhoeff-Van Gieson protocol. (J and K) Lung function was measured in naïve and day 9-infected animals. Arterial blood oxygen partial pressure (J) and O2 saturation (K) are shown.
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Related In: Results  -  Collection

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ppat-1004053-g007: CD11c-Cre/Ppargfl/fl mice have a reduced resistance to influenza virus infection despite an intact antiviral adaptive response.Ppargfl/fl and CD11c-Cre/Ppargfl/fl mice were infected i.t. with 250 pfu PR8 influenza virus. Loss of body weight (A), temperature (B) and survival (C) was monitored. Values indicate mean ± SEM of 9–10 mice per group. (D–K) For the characterization of the anti-viral immune response, Ppargfl/fl and CD11cCre/Ppargfl/fl mice were infected i.t. with 50 pfu PR8 influenza virus. Symbols represent values of individual mice and the mean is indicated. (D) The virus titers in the lung were determined at d3, d5 and d9 after infection. (E) Total numbers of influenza NP34-specific CD8+ T cells in the BAL were analyzed at d10 post-infection. (F) Influenza HA-specific IgG2c antibody concentrations in the BAL at d13 post-infection were determined by ELISA. Values indicate mean ± SEM of 4–5 mice per group. (G) Total protein in the BAL was measured at indicated time points. (H) Cytospins of BAL isolated from infected mice at d9 were stained with Oil Red O. Micrographs were taken at 63× magnification. Representative pictures of 2 individual mice are shown. (I) Panels show lung sections of day 9-infected mice stained using the Verhoeff-Van Gieson protocol. (J and K) Lung function was measured in naïve and day 9-infected animals. Arterial blood oxygen partial pressure (J) and O2 saturation (K) are shown.
Mentions: Mice lacking Pparg specifically in macrophages (LysM-Cre/Ppargfl/fl) develop pulmonary alveolar proteinosis [35]. Moreover, using CD11c-Cre/Ppargfl/fl mice that lack Pparg in AM and DCs, we recently found that development of AM is arrested in an immature state with a defect in surfactant catabolism and lipid metabolism while development of DC subsets remained unaffected (data not shown). To determine whether absence of functional AM affects resistance of CD11c-Cre/Ppargfl/fl mice to respiratory viral infection, we infected WT and CD11c-Cre/Ppargfl/fl mice with influenza virus PR8. Compared to WT, CD11c-Cre/Ppargfl/fl mice showed an earlier onset and more pronounced loss of body weight and body temperature (Figure 7A, B) associated with increased lethality (Figure 7C), although lung virus titers were insignificantly elevated (Figure 7D). Besides a slightly increased number of neutrophils, recruitment of inflammatory cells to the lung was in general normal in CD11c-Cre/Ppargfl/fl mice (Figure S6). Moreover, we found similar frequencies and total numbers of anti-viral CD8+ T cells as well as IFNγ-producing CD4+ and CD8+ T cells (Figure 7E and Figure S6) indicating that DC-mediated T cell priming and effector responses were unaffected in CD11c-Cre/Ppargfl/fl mice. Likewise, levels of anti-influenza HA-specific antibody levels (i.e. IgG2c, IgA and IgG1) were comparable in BAL and serum of CD11c-Cre/Ppargfl/fl and WT mice (Figure 7F and Figure S6). Together these results indicate that innate and adaptive anti-viral immune responses were largely intact in CD11c-Cre/Ppargfl/fl mice.

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