leptin and Orthomyxoviridae-Infections

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.

Topics: Alveolar Epithelial Cells; Animals; Dogs; Influenza A Virus, H1N1 Subtype; Leptin; Lung; Macrophages, Alveolar; Madin Darby Canine Kidney Cells; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Neutrophils; Orthomyxoviridae Infections; Receptors, Leptin

Obesity is associated with a high circulating leptin level and severe 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) infection. The mechanism for severe lung injury in obese patients and the specific treatment strategy remain elusive.. We studied the pathogenesis of A(H1N1)pdm09 infection in a mouse model of diet-induced obesity.. Obese mice had significantly higher initial pulmonary viral titer and mortality after challenge with A(H1N1)pdm09, compared with age-matched lean mice. Compared with lean mice, obese mice had heightened proinflammatory cytokine and chemokine levels and more severe pulmonary inflammatory damage. Furthermore, obese mice had a higher preexisting serum leptin level but a lower preexisting adiponectin level. Recombinant mouse leptin increased the interleukin 6 (IL-6) messenger RNA expression in mouse single-lung-cell preparations, mouse macrophages, and mouse lung epithelial cell lines infected with A(H1N1)pdm09. Administration of anti-leptin antibody improved the survival of infected obese mice, with associated reductions in pulmonary levels of the proinflammatory cytokines IL-6 and interleukin 1β but not the pulmonary viral titer.. Our findings suggest that preexisting high levels of circulating leptin contribute to the development of severe lung injury by A(H1N1)pdm09 in mice with diet-induced obesity. The therapeutic strategy of leptin neutralization for the reduction of proinflammatory responses and pulmonary damage in obese patients warrants further investigations.

Topics: Animals; Antibodies; Diet, High-Fat; Disease Models, Animal; Epithelium; Female; Influenza A Virus, H1N1 Subtype; Interleukin-1beta; Interleukin-6; Kaplan-Meier Estimate; Leptin; Lung; Macrophages; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Orthomyxoviridae Infections; Pandemics; Pneumonia; Recombinant Proteins; RNA, Messenger; Viral Load

A hallmark of energy restriction (ER) is a decrease in total body fat, which is thought to increase lifespan and maintain immune function. However, we have shown that during primary influenza infection, ER induces rapid weight loss, impairs natural killer (NK) cell function, and increases mortality in young and aged mice. To determine whether influenza-induced NK cell function could be restored in ER mice, young adult (6 mo) male C57BL/6 mice were fed an ER diet or re-fed (RF) control diet ad libitum for 2 wk before infection with PR8 influenza A. An initial hyperphagic response was observed in RF mice, characterized by increased food intake, rapid weight gain, and restoration of body fat and fat depots by 5-7 d of re-feeding to levels comparable to control ad libitum (AL) mice. Re-feeding improved survival and attenuated the decline in NK cell function during infection, evidenced by increased numbers, percentages, and CD69 expression by d 3 postinfection in RF mice. Interestingly, an altered metabolic phenotype was observed during infection of RF mice, with plasma leptin concentrations greater than in ER mice but less than in AL mice. In contrast, adiponectin concentrations of RF mice were lower than those of both ER and AL mice. These data suggest that re-feeding for a defined period before, and perhaps throughout, influenza season may provide the energy needed to counter the deleterious effects of ER on NK cell function, especially during exposure to newly emerging strains of influenza, for which vaccines are limited or unavailable.

Topics: Adipocytes; Adiponectin; Adiposity; Animals; Body Weight; Bone Marrow Cells; Caloric Restriction; Eating; Food; Influenza A virus; Killer Cells, Natural; Leptin; Male; Mice; Mice, Inbred C57BL; Orthomyxoviridae Infections

Obesity is associated with an impaired immune response, an increased susceptibility to bacterial infection, and a chronic increase in proinflammatory cytokines such as IL-6 and TNFalpha. However, few studies have examined the effect of obesity on the immune response to viral infections. Because infection with influenza is a leading cause of morbidity and mortality worldwide, we investigated the effect of obesity on early immune responses to influenza virus exposure. Diet-induced obese and lean control C57BL/6 mice were infected with influenza A/PR8/34, and lung pathology and immune responses were examined at d 0 (uninfected), 3, and 6, postinfection. Following infection, diet-induced obese mice had a significantly higher mortality rate than the lean controls and elevated lung pathology. Antiviral and proinflammatory cytokine mRNA production in the lungs of the infected mice was markedly different between obese and lean mice. IFNalpha and beta were only minimally expressed in the infected lungs of obese mice and there was a notable delay in expression of the proinflammatory cytokines IL-6 and TNFalpha. Additionally, obese mice had a substantial reduction in NK cell cytotoxicity. These data indicate that obesity inhibits the ability of the immune system to appropriately respond to influenza infection and suggests that obesity may lead to increased morbidity and mortality from viral infections.

Topics: Animals; Chemokine CCL2; Chemokine CCL5; Cytokines; Cytotoxicity, Immunologic; Diet; Insulin; Killer Cells, Natural; Leptin; Lung; Mice; Mice, Inbred C57BL; Obesity; Orthomyxoviridae; Orthomyxoviridae Infections; RNA, Messenger; Viral Load