Both patients with chronic obstructive pulmonary disease (COPD) as well as smokers are more susceptible to severe viral infections compared to healthy non-smoking people. Whilst instigating and aggravating disease, it is currently unclear why smoke exposure predisposed to severe viral infections. Here, we hypothesized that prior smoke exposure impairs immune responses against viral infections.

To test this hypothesis, female C57BL/6 mice were exposed to cigarette smoke or air twice a day for 24-28 days, during which mice were infected with X31 influenza or mock infected. Three or seven days after infection, myeloid and lymphoid immune cell populations, and mRNA expression in lung tissue were investigated by flow cytometry and RNAseq respectively.

We found that infected mice exposed to cigarette smoke lost significantly more weight than air exposed mice, demonstrating that smoke exposure resulted in more severe viral disease. To further examine this, transcriptome analysis and immune cell analysis revealed that smoke exposure delayed expression of genes in innate immunity pathways and inhibited repair responses on RNA level and resulted in prolonged neutrophil infiltration on cellular level. Moreover, delayed interferon gene expression was observed in combination with decreased clearance of viral RNA, indicating improper responses to the virus. Altogether, our data indicate that smoke exposure significantly delays innate immune responses against influenza, thereby possibly setting the stage for development of more severe disease. The results from this study will help to explain the susceptibility of patients with COPD to severe influenza disease and may reveal potential new therapeutic options.