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Title: Impaired clearance of influenza A virus in obese, leptin receptor deficient mice is independent of leptin signaling in the lung epithelium and macrophages.

Authors: Radigan, Kathryn A; Morales-Nebreda, Luisa; Soberanes, Saul; Nicholson, Trevor; Nigdelioglu, Recep; Cho, Takugo; Chi, Monica; Hamanaka, Robert B; Misharin, Alexander V; Perlman, Harris; Budinger, G R Scott; Mutlu, Gökhan M

Published In PLoS One, (2014)

Abstract: During the recent H1N1 outbreak, obese patients had worsened lung injury and increased mortality. We used a murine model of influenza A pneumonia to test the hypothesis that leptin receptor deficiency might explain the enhanced mortality in obese patients.We infected wild-type, obese mice globally deficient in the leptin receptor (db/db) and non-obese mice with tissue specific deletion of the leptin receptor in the lung epithelium (SPC-Cre/LepR fl/fl) or macrophages and alveolar type II cells (LysM-Cre/Lepr fl/fl) with influenza A virus (A/WSN/33 [H1N1]) (500 and 1500 pfu/mouse) and measured mortality, viral clearance and several markers of lung injury severity.The clearance of influenza A virus from the lungs of mice was impaired in obese mice globally deficient in the leptin receptor (db/db) compared to normal weight wild-type mice. In contrast, non-obese, SP-C-Cre+/+/LepR fl/fl and LysM-Cre+/+/LepR fl/fl had improved viral clearance after influenza A infection. In obese mice, mortality was increased compared with wild-type mice, while the SP-C-Cre+/+/LepR fl/fl and LysM-Cre+/+/LepR fl/fl mice exhibited improved survival.Global loss of the leptin receptor results in reduced viral clearance and worse outcomes following influenza A infection. These findings are not the result of the loss of leptin signaling in lung epithelial cells or macrophages. Our results suggest that factors associated with obesity or with leptin signaling in non-myeloid populations such as natural killer and T cells may be associated with worsened outcomes following influenza A infection.

PubMed ID: 25232724 Exiting the NIEHS site

MeSH Terms: Alveolar Epithelial Cells/physiology*; Alveolar Epithelial Cells/virology; Animals; Dogs; Influenza A Virus, H1N1 Subtype/immunology*; Leptin/physiology*; Lung/immunology; Lung/pathology; Lung/virology; Macrophages, Alveolar/physiology; Macrophages, Alveolar/virology*; Madin Darby Canine Kidney Cells; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Neutrophils/immunology; Neutrophils/virology; Orthomyxoviridae Infections/immunology*; Orthomyxoviridae Infections/metabolism; Orthomyxoviridae Infections/virology; Receptors, Leptin/genetics; Receptors, Leptin/metabolism

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