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.