Respiratory syncytial virus promotes allergic predisposition via gastrointestinal microbiome alteration

Respiratory syncytial virus (RSV) is a leading cause of childhood hospitalizations and increases the relative risk for the development of wheezing and asthma following acute bronchiolitis. Previously, we observed increased allergic predisposition following early life RSV infection in response to cockroach allergen (CRA) with a concurrent alteration in the gastrointestinal microbiome in mouse models of RSV infection and allergy. Importantly, differences in the gastrointestinal microbiome have been reported in children at a high risk for asthma. However, the effect of viral infection induced gastrointestinal microbiome alteration on allergic predisposition has not been studied. Our initial studies showed that early life RSV infection led to altered microbiome development that corresponded with disease development. We hypothesized that RSV-induced alteration of the microbiome can predispose infected animals to enhanced allergic inflammation. To address this, neonatal germ-free mice were colonized with normal microbiome from specific pathogen free mice with subsequent RSV infection followed by CRA modeling at 4 weeks post-infection. Colonization of germ-free neonatal mice protected the development of severe allergic asthma later in life, while an early life RSV infection of colonized mice reduced the protective effect of the microbiome by increasing airway hyperreactivity and T helper 2 induced responses. Taken together, our data indicate that early life RSV infection alters the neonatal microbiome leading to enhanced allergic predisposition. Supported by grants from NIH (R35 HL150682, R01 AI138348)