Serum Amyloid A3 is required for normal lung development and survival following influenza infection

• Published in: Scientific reports Vol. 8; no. 1; pp. 16571 - 13
• Main Authors: Ather, Jennifer L., Dienz, Oliver, Boyson, Jonathan E., Anathy, Vikas, Amiel, Eyal, Poynter, Matthew E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.11.2018; Nature Publishing Group
• Subjects: 13/21; 13/31; 14/63; 631/250; 631/250/1619; 64/60; Adaptive immunity; Amyloid; Animals; Apolipoproteins; Asthma; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Citrulline; Copy number; Gene expression; Gene Knockout Techniques; Glycolysis; Homeostasis; House dust; Humanities and Social Sciences; Infections; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype - pathogenicity; Interleukin 2; Lipopolysaccharides - adverse effects; Lung - growth & development; Lung - metabolism; Lung - virology; Lung diseases; Lung Diseases - genetics; Lung Diseases - pathology; Lung Diseases - virology; Lymphocytes T; Mice; multidisciplinary; Orthomyxoviridae Infections - genetics; Orthomyxoviridae Infections - metabolism; Proteins; Pyroglyphidae - immunology; Respiratory Hypersensitivity - genetics; Respiratory Hypersensitivity - immunology; Respiratory tract; Science; Science (multidisciplinary); Serum Amyloid A Protein - genetics; Serum Amyloid A Protein - metabolism; Survival Analysis; Swine flu; γ-Interferon; H1N1 Influenza Infection; Polyclonal Stimulation; Wild-type Littermates; Protein Citrullination; Adult-onset Obesity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-34901-x

Serum amyloid A (SAA) proteins are a family of acute phase apolipoproteins implicated to directly modulate innate and adaptive immune responses. However, new studies comparing endogenous SAAs and recombinant forms of these proteins have questioned the function of SAA in inflammation and immunity. We generated SAA3 knockout mice to evaluate the contribution of SAA3 to lung development and immune-mediated lung disease. While SAA3 deficiency does not affect the generation of house dust mite-induced allergic asthma, mice lacking SAA3 develop adult-onset obesity, intrinsic airway hyperresponsiveness, increased inflammatory and fibrotic gene expression in the lung, and elevated levels of lung citrullinated proteins. Polyclonally stimulated CD4 + T cells from SAA3−/− mice exhibit impaired glycolytic activity, decreased T H 2 and T H 1 cytokine secretion, and elevated IL-17A production compared to wild type cells. Polyclonally stimulated CD8 + T cells from SAA3−/− mice also exhibit impaired glycolytic activity as well as a diminished capacity to produce IL-2 and IFNγ. Finally, SAA3−/− mice demonstrate increased mortality in response to H1N1 influenza infection, along with higher copy number of viral RNAs in the lung, a lack of CD8 + T cell IFNγ secretion, and decreased flu-specific antibodies. Our findings indicate that endogenous SAA3 regulates lung development and homeostasis, and is required for protection against H1N1 influenza infection.