GM-CSF modulates pulmonary resistance to influenza A infection

• Published in: Antiviral research Vol. 92; no. 2; pp. 319 - 328
• Main Authors: 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 C.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.11.2011; Elsevier
• Subjects: Alveolar macrophages; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Epithelial cells; Female; GM-CSF; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Human viral diseases; Infectious diseases; Influenza; Influenza A Virus, H1N1 Subtype - immunology; Influenza A Virus, H1N1 Subtype - pathogenicity; Lung - immunology; Lung - pathology; Lymphocytes - immunology; Macrophages - immunology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Orthomyxoviridae Infections - mortality; Orthomyxoviridae Infections - pathology; Orthomyxoviridae Infections - prevention & control; Pharmacology. Drug treatments; Scavenger receptors; SP-A; Survival Analysis; Viral diseases; Viral diseases of the respiratory system and ent viral diseases; ffc; SFTPC or SP-C; Epithelial cells; tet-GM; GM; SP-R210; Alveolar macrophages; MARCO; SR-A; GM-CSF; Influenza; SP-A; Scavenger receptors; SCG1A1; pfu; Lung; Influenza A; Biological receptor; Treatment resistance; Respiratory disease; H1N1 influenza; Mortality; Rodentia; Cytokine; Radical scavenger; Infection; Vertebrata; Mammalia; Mouse; Viral disease; Pulmonary alveolus; Animal; Epithelial cell; Granulocyte macrophage colony stimulating factor
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2011.08.022

► Early GM-CSF expression in conditional mice protects against influenza A virus. ► GM-CSF links innate and adaptive immunity against influenza. ► Unregulated GM-CSF causes lung immunopathology secondary to influenza infection. ► GM-CSF enhances expression of SP-R210 and MARCO on alveolar macrophages. ► MARCO decreases resistance to influenza infection. 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 4 ffc 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.