Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization

• Published in: The Journal of clinical investigation Vol. 130; no. 6; pp. 3021 - 3037
• Main Authors: Shibata, Takehiko, Makino, Airi, Ogata, Ruiko, Nakamura, Shigeki, Ito, Toshihiro, Nagata, Kisaburo, Terauchi, Yoshihiko, Oishi, Taku, Fujieda, Mikiya, Takahashi, Yoshimasa, Ato, Manabu
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.06.2020
• Subjects: Alveoli; Animals; Antibacterial activity; Antibacterial agents; Axl protein; Bacterial infections; Biomedical research; Caspase-1; Cytokines - genetics; Cytokines - immunology; Disease susceptibility; Genotype & phenotype; Health aspects; Infection; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Interleukin 18; Killer cells; Macrophages; Macrophages, Alveolar - immunology; Macrophages, Alveolar - microbiology; Macrophages, Alveolar - pathology; Macrophages, Alveolar - virology; Male; Mice; Mice, Knockout; Natural killer cells; Neutrophils; Phenotypes; Pneumococcal pneumonia; Pneumonia; Pneumonia, Pneumococcal - genetics; Pneumonia, Pneumococcal - immunology; Pneumonia, Pneumococcal - pathology; Pneumonia, Pneumococcal - virology; Protein expression; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - immunology; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - immunology; Respiratory syncytial virus; Respiratory Syncytial Virus Infections - genetics; Respiratory Syncytial Virus Infections - immunology; Respiratory Syncytial Virus Infections - pathology; Respiratory Syncytial Viruses - immunology; Software industry; Streptococcus infections; Therapeutic applications; Tumor necrosis factor-α; Virus diseases; γ-Interferon; United States; Japan; Infectious disease; Innate immunity; Immunology; Cytokines
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI125505

Patients with respiratory syncytial virus (RSV) infection exhibit enhanced susceptibility to subsequent pneumococcal infections. However, the underlying mechanisms involved in this increased susceptibility remain unclear. Here, we identified potentially novel cellular and molecular cascades triggered by RSV infection to exacerbate secondary pneumococcal pneumonia. RSV infection stimulated the local production of growth arrest-specific 6 (Gas6). The Gas6 receptor Axl was crucial for attenuating pneumococcal immunity in that the Gas6/Axl blockade fully restored antibacterial immunity. Mechanistically, Gas6/Axl interaction regulated the conversion of alveolar macrophages from an antibacterial phenotype to an M2-like phenotype that did not exhibit antibacterial activity, and the attenuation of caspase-1 activation and IL-18 production in response to pneumococcal infection. The attenuated IL-18 production failed to drive both NK cell-mediated IFN-γ production and local NO and TNF-α production, which impair the control of bacterial infection. Hence, the RSV-mediated Gas6/Axl activity attenuates the macrophage-mediated protection against pneumococcal infection. The Gas6/Axl axis could be a potentially novel therapeutic target for RSV-associated secondary bacterial infection.