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Biochem Biophys Res Commun. 2019 Apr 6. pii: S0006-291X(19)30618-7. doi: 10.1016/j.bbrc.2019.03.211. [Epub ahead of print]

Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice.

Author information

1
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan; Japan Society for the Promotion of Science, Tokyo, Japan.
2
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. Electronic address: ishii@keio.jp.
3
Department of Oral Microbiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
4
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
5
Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
6
Center for Infectious Diseases and Infection Control, Keio University School of Medicine, Tokyo, Japan.

Abstract

Increasing evidence indicates that obesity is a risk factor for increased severity of influenza virus infection. However, its precise immunological mechanism is not fully understood. To investigate this, diet-induced obese (DIO) mice were established by feeding C57BL/6 male mice a high-fat diet for 16 weeks. DIO and lean control mice were infected intranasally with 3000 pfu of influenza A virus (IAV) (PR8/H1N1). Interestingly, we found adipose tissue located along the bronchus in naïve DIO mice. In addition, the Nos2 level was significantly higher and Arg1 level was significantly lower in lung macrophages of naïve DIO mice, consistent with an M1-skewed phenotype. The survival rate and body weight of DIO mice infected with IAV were significantly lower than those of lean control mice and associated with higher viral load in the lungs of DIO mice. Histopathological analysis demonstrated higher numbers of inflammatory cells in the lungs of DIO mice after IAV infection. Levels of cytokines, including TNF-α, IL-6, IL-10, and type I IFN (IFN-α and IFN-β), in bronchoalveolar lavage fluid (BALF) were altered after IAV infection; in particular, IFN-α and IFN-β levels were significantly suppressed in the BALF of DIO mice. In vitro, bone marrow-derived macrophages were stimulated with ligands of toll-like receptor (TLR) 7/8, a pattern recognition receptor for single-stranded RNA, and levels of TNF-α, IL-6, and IL-10 were similarly altered. In addition, levels of IFN-α and IFN-β were significantly lower in culture supernatants of alveolar macrophages sorted from naïve DIO mice and infected with IAV, compared to those in macrophages sorted from lean control mice. Collectively, these results suggest that macrophages may be the main contributors to poor outcomes of influenza virus infection in obesity.

KEYWORDS:

Alveolar macrophages; Diet-induced obesity; Influenza; Type I interferon

PMID:
30967261
DOI:
10.1016/j.bbrc.2019.03.211

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