Obese mice have increased morbidity and mortality compared to non‐obese mice during infection with the 2009 pandemic H1N1 influenza virus

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Abstract

Please cite this paper as: Easterbrook et al. (2011) Obese mice have increased morbidity and mortality compared to non‐obese mice during infection with the 2009 pandemic H1N1 influenza virus. Influenza and Other Respiratory Viruses 5(6), 418–425.

Background Obesity has been identified as an independent risk factor for severe or fatal infection with 2009 pandemic H1N1 influenza (2009 pH1N1), but was not previously recognized for previous pandemic or seasonal influenza infections.

Objectives Our aim was to evaluate the role of obesity as an independent risk factor for severity of infection with 2009 pH1N1, seasonal H1N1, or a pathogenic H1N1 influenza virus.

Methods Diet‐induced obese (DIO) and their non‐obese, age‐matched control counterparts were inoculated with a 2009 pH1N1, A/California/04/2009 (CA/09), current seasonal H1N1, A/NY/312/2001 (NY312), or highly pathogenic 1918‐like H1N1, A/Iowa/Swine/1931 (Sw31), virus.

Results Following inoculation with CA/09, DIO mice had higher mortality (80%) than control mice (0%) and lost more weight during infection. No effect of obesity on morbidity and mortality was observed during NY312 or Sw31 infection. Influenza antigen distribution in the alveolar regions of the lungs was more pronounced in DIO than control mice during CA/09 infection at 3 days post‐inoculation (dpi), despite similar virus titers. During CA/09 infection, localized interferon‐β and proinflammatory cytokine protein responses in the lungs were significantly lower in DIO than control mice. Conversely, serum cytokine concentrations were elevated in DIO, but not control mice following infection with CA/09. The effect of obesity on differential immune responses was abrogated during NY312 or Sw31 infection.

Conclusions Together, these data support epidemiologic reports that obesity may be a risk factor for severe 2009 pandemic H1N1 influenza infection, but the role of obesity in seasonal or highly virulent pandemic influenza infection remains unclear.

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Most cited references 24

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Diet-induced type II diabetes in C57BL/6J mice.

Richard Surwit, Cynthia M. Kuhn, Christina Cochrane … (1988)

We investigated the effects of diet-induced obesity on glucose metabolism in two strains of mice, C57BL/6J and A/J. Twenty animals from each strain received ad libitum exposure to a high-fat high-simple-carbohydrate diet or standard Purina Rodent Chow for 6 mo. Exposure to the high-fat, high-simple-carbohydrate, low-fiber diet produced obesity in both A/J and C57BL/6J mice. Whereas obesity was associated with only moderate glucose intolerance and insulin resistance in A/J mice, obese C57BL/6J mice showed clear-cut diabetes with fasting blood glucose levels of greater than 240 mg/dl and blood insulin levels of greater than 150 microU/ml. C57BL/6J mice showed larger glycemic responses to stress and epinephrine in the lean state than AJ mice, and these responses were exaggerated by obesity. These data suggest that the C57BL/6J mouse carries a genetic predisposition to develop non-insulin-dependent (type II) diabetes. Furthermore, altered glycemic response to adrenergic stimulation may be a biologic marker for this genetic predisposition to develop type II diabetes.

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Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus.

Alexia Smith, Patricia Sheridan, Joyce Harp … (2007)

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.

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Genetic vulnerability to diet-induced obesity in the C57BL/6J mouse: physiological and molecular characteristics.

Sheila Collins, Tonya L Martin, Richard Surwit … (2004)

The development of the metabolic syndrome in an increasing percentage of the populations of Western societies, particularly in the United States, requires valid models for establishing basic biochemical changes and performing preclinical studies on potential drug targets. The C57BL/6J mouse has become an important model for understanding the interplay between genetic background and environmental challenges such as high-fat/high-calorie diets that predispose to the development of the metabolic syndrome. This review highlights metabolic and signal transduction features that are altered during the course of disease progression, many of which mirror the human situation. Copyright 2004 Elsevier Inc.

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Author and article information

Journal

Journal ID (nlm-ta): Influenza Other Respir Viruses

Journal ID (iso-abbrev): Influenza Other Respir Viruses

Journal ID (doi): 10.1111/(ISSN)1750-2659

Journal ID (publisher-id): IRV

Title: Influenza and Other Respiratory Viruses

Publisher: Blackwell Publishing Ltd (Oxford, UK )

ISSN (Print): 1750-2640

ISSN (Electronic): 1750-2659

Publication date (Electronic): 18 April 2011

Publication date (Print): November 2011

Volume: 5

Issue: 6 ( doiID: 10.1111/irv.2011.5.issue-6 )

Pages: 418-425

Affiliations

[ ¹ ]Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Author notes

[*]Jeffery K. Taubenberger, MD, PhD, Laboratory of Infectious Diseases, NIAID, NIH, 33 North Drive, MSC 3203, Bethesda, MD 20892‐3203, USA. E‐mail: taubenbergerj@ 123456niaid.nih.gov