Although it is known that obesity raises the risk of infection and disease severity for several infectious agents such as influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), the underlying mechanisms are not well established. A study in Science Advances uses a new obese ferret model to provide insights into the mechanisms of influenza disease severity in the context of obesity.

First, to develop the diet-induced obese model, the investigators fed male ferrets with a calorically dense diet ad libitum for 12 weeks. The ferrets gained more weight than the control ferrets – fed a standard chow once daily – and by the end of the diet period developed central features of metabolic syndrome, including an increase in fasting glucose and total cholesterol. Next, the team inoculated control and obese ferrets with H1N1 virus, and monitored the weight, body temperature and clinical signs of the animals for 12 days post infection (dpi). Compared with control animals, obese ferrets lost more weight, had higher body temperature during the acute phase of infection and developed more symptoms such as coughing and nasal discharge. Further analyses showed increased damage, inflammation, immune infiltration and overall higher viral titers in the lungs of obese animals compared to controls. These findings show that the diet-induced obese ferret model recapitulates key features of obesity and metabolic dysfunction seen in humans and develop more severe influenza disease.

To uncover potential new mechanisms, the researchers performed qPCR on lung tissues of obese and control ferrets at 6 dpi, using a newly designed a panel of primers targeting lung function and immunity genes. Gene expression analysis revealed that obese animals had a dysregulated antiviral response, with upregulation of key inflammatory mediators, such as Il1a and Nos2, and downregulation of genes involved in the innate interferon (IFN) response.

In addition, the team performed transmission experiments which revealed that obesity affected viral transmission of avian-like H9N2 influenza virus, with obese ferrets being more susceptible to infection through direct contact.

Altogether, these findings support the use of the obese ferret model to better understand the impact of obesity on influenza disease severity and community transmission, and to refine vaccines and therapeutics for high-risk individuals.

Original reference: Meliopoulos, V. et al. Sci. Adv 10, eadk9137 (2024)