Allergic inflammation hinders synergistic viral-bacterial co-infection in C57BL/6 mice

Asthma is a chronic airways disease that can be exacerbated during respiratory infections. Our previous findings that the inflammatory state of allergic airways at the time of influenza A virus (IAV) infection in combination with epidemiologic findings that asthmatics were less likely to suffer from severe influenza during the 2009 pandemic suggest that additional complications of influenza, such as increased susceptibility to bacterial superinfection, may be mitigated in the allergic host. To test this hypothesis, we developed a murine model of ‘triple-disease’ in which mice were first rendered allergic to Aspergillus fumigatus and co-infected with IAV and Streptococcus pneumoniae seven days apart. Significant alterations to known synergistic effects of co-infection were noted in the allergic mice including reduced morbidity and mortality, bacterial burden, maintenance of alveolar macrophages, and reduced lung inflammation and damage. The lung microbiome of allergic mice differed from that of non-allergic mice during co-infection. To investigate the impact of the microbiome on the pathogenesis of lung disease, we induced a perturbation with a short course of fluoroquinolone antibiotic that is often prescribed for lung infections. A significant change in the microbiome was complemented with alterations to the inflammatory profile and a drastic increase in pro-inflammatory cytokines in allergic mice which were now susceptible to severe disease from IAV and S. pneumoniae co-infection. Our data suggest that responses to co-infection in allergic hosts likely depends on the immune and microbiome states and that antibiotics should be used with caution in individuals with underlying chronic lung disease. Author Summary Asthma is a condition of the lungs that affects millions worldwide. Traditionally, respiratory infections are considered to have a negative impact on asthmatics. However, epidemiological data surrounding the 2009 influenza pandemic suggest that asthmatics may be better equipped to counter severe influenza including bacterial pneumonia. Herein, we introduce a novel mouse model system designed to recapitulate an influenza virus and Streptococcal co-infection in a host with fungal asthma. We found that underlying allergic asthma protects against severe disease induced by co-infection. Mice with underlying allergic inflammation had reduced damage to the lungs and did not show signs of respiratory distress. Among the differences noted in the allergic mice that were protected from viral and bacterial co-infection, was the lung microbiome. Allergic mice lost their protection from co-infection after we perturbed their lung microbiome with antibiotics suggesting that the lung microbiome plays a role in host immunity against invading pathogens.