Allergic Airway Disease Prevents Lethal Synergy of Influenza A Virus-Streptococcus pneumoniae Coinfection

Abstract

Fatal outcomes following influenza infection are often associated with secondary bacterial infections. Allergic airway disease (AAD) is known to influence severe complications from respiratory infections, and yet the mechanistic effect of AAD on influenza virus-Streptococcus pneumoniae coinfection has not been investigated previously. We examined the impact of AAD on host susceptibility to viral-bacterial coinfections. We report that AAD improved survival during coinfection when viral-bacterial challenge occurred 1 week after AAD. Counterintuitively, mice with AAD had significantly deceased proinflammatory responses during infection. Specifically, both CD4+ and CD8+ T cell interferon gamma (IFN-γ) responses were suppressed following AAD. Resistance to coinfection was also associated with strong transforming growth factor β1 (TGF-β1) expression and increased bacterial clearance. Treatment of AAD mice with IFN-γ or genetic deletion of TGF-β receptor II expression reversed the protective effects of AAD. Using a novel triple-challenge model system, we show for the first time that AAD can provide protection against influenza virus-S. pneumoniae coinfection through the production of TGF-β that suppresses the influenza virus-induced IFN-γ response, thereby preserving antibacterial immunity. IMPORTANCE Asthma has become one of the most common chronic diseases and has been identified as a risk factor for developing influenza. However, the impact of asthma on postinfluenza secondary bacterial infection is currently not known. Here, we developed a novel triple-challenge model of allergic airway disease, primary influenza infection, and secondary Streptococcus pneumoniae infection to investigate the impact of asthma on susceptibility to viral-bacterial coinfections. We report for the first time that mice recovering from acute allergic airway disease are highly resistant to influenza-pneumococcal coinfection and that this resistance is due to inhibition of influenza virus-mediated impairment of bacterial clearance. Further characterization of allergic airway disease-associated resistance against postinfluenza secondary bacterial infection may aid in the development of prophylactic and/or therapeutic treatment against coinfection.

Interleukin-4 protects mice against lethal influenza and Streptococcus pneumoniae co-infected pneumonia

“…Consistent with this, another study also showed that allergic airway disease (AAD) improved survival of coinfected mice. Mice with AAD had significantly deceased proinflammatory responses during infection [36]. The researches above suggest that IL-4 may play a protective role in influenza and S. pneumoniae co-infection via significant anti-inflammatory effect, which was confirmed in our study.…”

Insights Into Type I and III Interferons in Asthma and Exacerbations

“…Furthermore, these results were repeated with HDM-sensitized mice, which also displayed lower bacterial burden and mortality in response to influenza/ S. pneumoniae co-infection compared with non-sensitized mice. The mice with AAD produced more TGFβ even before influenza infection, and this protection from infectious disease was ablated in mice with deletion of TGFβRII ( 123 ). TGFβ is commonly up-regulated in asthma ( 124 ), and is thus likely to contribute to protection from viral/bacterial co-infection in humans with asthma as well.…”

Influenza in High-Risk Hosts—Lessons Learned from Animal Models

“…Allergic mice show prior airway inflammation increases resistance to subsequent influenza infection-a phenomenon opposite of what is seen in epidemiological studies of human asthmatics (Ishikawa et al 2012;Samarasinghe et al 2014;Furuya et al 2015;Kawaguchi et al 2017). This protection is conferred to secondary bacterial coinfections caused by heightened TGF-β expression in asthmatic mice suppressing IFN-γ and promoting induction of robust antibacterial responses (Roberts et al 2019). The protective effects of the allergic airway ameliorate damage to the epithelial surface, increase mucus production, and reduce weight loss on influenza infection during the peak allergic response and heightens eosinophilic responses capable of viral clearance (Samarasinghe et al 2014(Samarasinghe et al , 2017.…”