Asthma and chronic obstructive pulmonary disease (COPD) represent two classes of chronic obstructive lung disorders that may share some similar immunologic mechanisms of disease. Asthma is a complex human disease characterized by airway hyperresponsiveness (AHR) and inflammation, whereas COPD is marked by progressive emphysematic changes in the lung. Recently it has been shown that advanced COPD is characterized by lymphoid follicles, drawing attention to immunological mechanisms in COPD. Despite numerous studies in mice to elucidate the immunologic mechanisms of asthma, sufficient current treatment options are limited. Clinically, many asthma patients fail to satisfactorily respond to standard steroid therapy, and this type of steroid-resistant, severe asthma has been linked to the presence of neutrophilic inflammation in the lung. The role of neutrophils, macrophages, and their secreted proteases in COPD needs to be better defined. Recently, the T lymphocyte subset T_H17 was shown to play a role in regulating neutrophilic and macrophage inflammation in the lung, suggesting a potential role for T_H17 cells in severe, steroid-insensitive asthma and COPD.

Seasonal influenza infection presents a major strain on the health care system. Influenza infection has pandemic potential, which has been repeatedly observed during the last century. Severe disease may occur in the young, elderly, those with pre-existing lung disease, and in previously healthy individuals. A common cause of severe influenza pathogenesis is super-infection with bacterial pathogens, namely Staphylococcus aureus and Streptococcus pneumoniae. A great deal of recent research has focused on the immune pathways involved in influenza-induced susceptibility to secondary bacterial pneumonia. Both innate and adaptive anti-bacterial host defenses are impaired in the context of preceding influenza virus infection. The goal of this minireview is to highlight these findings and synthesize these data into a shared central theme of pathogenesis.

Influenza infection is widespread in the United States and the world. Despite low mortality rates due to infection, morbidity is common and little is known about the molecular events involved in recovery. Influenza infection results in persistent distal lung remodeling, and the mechanism(s) involved are poorly understood. Recently IL-22 has been found to mediate epithelial repair. We propose that IL-22 is critical for recovery of normal lung function and architecture after influenza infection. Wild-type and IL-22(-/-) mice were infected with influenza A PR8/34 H1N1 and were followed up for up to 21 days post infection. IL-22 receptor was localized to the airway epithelium in naive mice but was expressed at the sites of parenchymal lung remodeling induced by influenza infection. IL-22(-/-) mice displayed exacerbated lung injury compared with wild-type mice, which correlated with decreased lung function 21 days post infection. Epithelial metaplasia was observed in wild-type mice but was not evident in IL-22(-/-) animals that were characterized with an increased fibrotic phenotype. Gene expression analysis revealed aberrant expression of epithelial genes involved in repair processes, among changes in several other biological processes. These data indicate that IL-22 is required for normal lung repair after influenza infection. IL-22 represents a novel pathway involved in interstitial lung disease.

Pneumonia is a leading cause of death worldwide. Staphylococcal aureus can be a cause of severe pneumonia alone or a common pathogen in secondary pneumonia following influenza. Recently, we reported that preceding influenza attenuated the Type 17 pathway, increasing the lung’s susceptibility to secondary infection. IL-1β is known to regulate host defense, including playing a role in Th17 polarization. We examined whether IL-1β signaling is required for S. aureus host defense and whether influenza infection impacted S. aureus–induced IL-1β production and subsequent Type 17 pathway activation. Mice were challenged with S. aureus (USA 300), with or without preceding Influenza A/PR/8/34 H1N1 infection. IL-1R1^−/− mice had significantly higher S. aureus burden, increased mortality, and decreased Type 17 pathway activation following S. aureus challenge. Coinfected mice had significantly decreased IL-1β production versus S. aureus infection alone at early time points following bacterial challenge. Preceding influenza did not attenuate S. aureus–induced inflammasome activation, but there was early suppression of NF-κB activation, suggesting an inhibition of NF-κB–dependent transcription of pro–IL-1β. Furthermore, overexpression of IL-1β in influenza and S. aureus–coinfected mice rescued the induction of IL-17 and IL-22 by S. aureus and improved bacterial clearance. Finally, exogenous IL-1β did not significantly rescue S. aureus host defense during coinfection in IL-17RA^−/− mice or in mice in which IL-17 and IL-22 activity were blocked. These data reveal a novel mechanism by which Influenza A inhibits S. aureus–induced IL-1β production, resulting in attenuation of Type 17 immunity and increased susceptibility to bacterial infection.

Suppression of type 17 immunity by type I interferon (IFN) during influenza A infection has been shown to enhance susceptibility to secondary bacterial pneumonia. Although this mechanism has been described in coinfection with gram-positive bacteria, it is unclear whether similar mechanisms may impair lung defense against gram-negative infections. Furthermore, precise delineation of the duration of type I IFN-associated susceptibility to bacterial infection remains underexplored. Therefore, we investigated the effects of preceding influenza A virus infection on subsequent challenge with the gram-negative bacteria Escherichia coli or Pseudomonas aeruginosa and the temporal association between IFN expression with susceptibility to Staphylococcus aureus challenge in a mouse model of influenza and bacterial coinfection. Here we demonstrate that preceding influenza A virus led to increased lung E. coli and P. aeruginosa bacterial burden, which was associated with suppression of type 17 immunity and attenuation of antimicrobial peptide expression. Enhanced susceptibility to S. aureus coinfection ceased at day 14 of influenza infection, when influenza-associated type I IFN levels had returned to baseline levels, further suggesting a key role for type I IFN in coinfection pathogenesis. These findings further implicate type I IFN-associated suppression of type 17 immunity and antimicrobial peptide production as a conserved mechanism for enhanced susceptibility to both gram-positive and gram-negative bacterial coinfection during influenza infection.