GM-CSF modulates pulmonary resistance to influenza A infection

Zvjezdana Sever-Chroneos, Aditi Murthy, Jeremy Davis, Jon Matthew Florence, Anna Kurdowska, Agnieszka Krupa, Jay W. Tichelaar, Mitchell R. White, Kevan L. Hartshorn, Lester Kobzik, Jeffrey A. Whitsett, Zissis Chroneos

Research output: Contribution to journalArticle

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Abstract

Alveolar type II epithelial or other pulmonary cells secrete GM-CSF that regulates surfactant catabolism and mucosal host defense through its capacity to modulate the maturation and activation of alveolar macrophages. GM-CSF enhances expression of scavenger receptors MARCO and SR-A. The alveolar macrophage SP-R210 receptor binds the surfactant collectin SP-A mediating clearance of respiratory pathogens. The current study determined the effects of epithelial-derived GM-CSF in host resistance to influenza A pneumonia. The results demonstrate that GM-CSF enhanced resistance to infection with 1.9×10 4ffc of the mouse-adapted influenza A/Puerto Rico/8/34 (PR8) H1N1 strain, as indicated by significant differences in mortality and mean survival of GM-CSF-deficient (GM -/-) mice compared to GM -/- mice in which GM-CSF is expressed at increased levels. Protective effects of GM-CSF were observed both in mice with constitutive and inducible GM-CSF expression under the control of the pulmonary-specific SFTPC or SCGB1A1 promoters, respectively. Mice that continuously secrete high levels of GM-CSF developed desquamative interstitial pneumonia that impaired long-term recovery from influenza. Conditional expression of optimal GM-CSF levels at the time of infection, however, resulted in alveolar macrophage proliferation and focal lymphocytic inflammation of distal airways. GM-CSF enhanced alveolar macrophage activity as indicated by increased expression of SP-R210 and CD11c. Infection of mice lacking the GM-CSF-regulated SR-A and MARCO receptors revealed that MARCO decreases resistance to influenza in association with increased levels of SP-R210 in MARCO -/- alveolar macrophages. In conclusion, GM-CSF enhances early host resistance to influenza. Targeting of MARCO may reinforce GM-CSF-mediated host defense against pathogenic influenza.

Original languageEnglish (US)
Pages (from-to)319-328
Number of pages10
JournalAntiviral Research
Volume92
Issue number2
DOIs
StatePublished - Nov 1 2011

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Granulocyte-Macrophage Colony-Stimulating Factor
Human Influenza
Lung
Infection
Alveolar Macrophages
Surface-Active Agents
Collectins
Scavenger Receptors
Puerto Rico
Interstitial Lung Diseases
Pneumonia

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Virology

Cite this

Sever-Chroneos, Z., Murthy, A., Davis, J., Florence, J. M., Kurdowska, A., Krupa, A., ... Chroneos, Z. (2011). GM-CSF modulates pulmonary resistance to influenza A infection. Antiviral Research, 92(2), 319-328. https://doi.org/10.1016/j.antiviral.2011.08.022
Sever-Chroneos, Zvjezdana ; Murthy, Aditi ; Davis, Jeremy ; Florence, Jon Matthew ; Kurdowska, Anna ; Krupa, Agnieszka ; Tichelaar, Jay W. ; White, Mitchell R. ; Hartshorn, Kevan L. ; Kobzik, Lester ; Whitsett, Jeffrey A. ; Chroneos, Zissis. / GM-CSF modulates pulmonary resistance to influenza A infection. In: Antiviral Research. 2011 ; Vol. 92, No. 2. pp. 319-328.
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Sever-Chroneos, Z, Murthy, A, Davis, J, Florence, JM, Kurdowska, A, Krupa, A, Tichelaar, JW, White, MR, Hartshorn, KL, Kobzik, L, Whitsett, JA & Chroneos, Z 2011, 'GM-CSF modulates pulmonary resistance to influenza A infection', Antiviral Research, vol. 92, no. 2, pp. 319-328. https://doi.org/10.1016/j.antiviral.2011.08.022

GM-CSF modulates pulmonary resistance to influenza A infection. / Sever-Chroneos, Zvjezdana; Murthy, Aditi; Davis, Jeremy; Florence, Jon Matthew; Kurdowska, Anna; Krupa, Agnieszka; Tichelaar, Jay W.; White, Mitchell R.; Hartshorn, Kevan L.; Kobzik, Lester; Whitsett, Jeffrey A.; Chroneos, Zissis.

In: Antiviral Research, Vol. 92, No. 2, 01.11.2011, p. 319-328.

Research output: Contribution to journalArticle

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AU - Sever-Chroneos, Zvjezdana

AU - Murthy, Aditi

AU - Davis, Jeremy

AU - Florence, Jon Matthew

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AU - Krupa, Agnieszka

AU - Tichelaar, Jay W.

AU - White, Mitchell R.

AU - Hartshorn, Kevan L.

AU - Kobzik, Lester

AU - Whitsett, Jeffrey A.

AU - Chroneos, Zissis

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N2 - Alveolar type II epithelial or other pulmonary cells secrete GM-CSF that regulates surfactant catabolism and mucosal host defense through its capacity to modulate the maturation and activation of alveolar macrophages. GM-CSF enhances expression of scavenger receptors MARCO and SR-A. The alveolar macrophage SP-R210 receptor binds the surfactant collectin SP-A mediating clearance of respiratory pathogens. The current study determined the effects of epithelial-derived GM-CSF in host resistance to influenza A pneumonia. The results demonstrate that GM-CSF enhanced resistance to infection with 1.9×10 4ffc of the mouse-adapted influenza A/Puerto Rico/8/34 (PR8) H1N1 strain, as indicated by significant differences in mortality and mean survival of GM-CSF-deficient (GM -/-) mice compared to GM -/- mice in which GM-CSF is expressed at increased levels. Protective effects of GM-CSF were observed both in mice with constitutive and inducible GM-CSF expression under the control of the pulmonary-specific SFTPC or SCGB1A1 promoters, respectively. Mice that continuously secrete high levels of GM-CSF developed desquamative interstitial pneumonia that impaired long-term recovery from influenza. Conditional expression of optimal GM-CSF levels at the time of infection, however, resulted in alveolar macrophage proliferation and focal lymphocytic inflammation of distal airways. GM-CSF enhanced alveolar macrophage activity as indicated by increased expression of SP-R210 and CD11c. Infection of mice lacking the GM-CSF-regulated SR-A and MARCO receptors revealed that MARCO decreases resistance to influenza in association with increased levels of SP-R210 in MARCO -/- alveolar macrophages. In conclusion, GM-CSF enhances early host resistance to influenza. Targeting of MARCO may reinforce GM-CSF-mediated host defense against pathogenic influenza.

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Sever-Chroneos Z, Murthy A, Davis J, Florence JM, Kurdowska A, Krupa A et al. GM-CSF modulates pulmonary resistance to influenza A infection. Antiviral Research. 2011 Nov 1;92(2):319-328. https://doi.org/10.1016/j.antiviral.2011.08.022