Defective interferon amplification and impaired host responses against influenza virus in obese mice.

Abstract

Obesity is a major risk factor that increases morbidity and mortality upon infection. Although type I and type III interferon (IFN)-induced innate immune responses represent the first line of defense against viral infections, their functionality in the context of metabolic disorders remains largely obscure. This study aimed to investigate IFN responses upon respiratory viral infection in obese mice. The activation of IFNs as well as IFN regulatory factors (IRFs) upon H3N2 influenza infection in mice upon high-fat-diet feeding was investigated. Influenza infection of obese mice was characterized by higher mortalities. In-depth analysis revealed impaired induction of both type I and type III IFNs as well as markedly reduced IFN responses. Notably, it was found that IRF7 gene expression in obese animals was reduced in homeostasis, and its induction by the virus was strongly attenuated. The results suggest that the attenuated IRF7 expression and induction are responsible for the reduced expression levels of type I and III IFNs and, thus, for the higher susceptibility and severity of respiratory infections in obese mice.