SUMMARY Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Despite broad literature including basic and translational scientific studies, many gaps in our understanding of host-pathogen interactions remain. In this review, pathogen virulence factors that drive lung infection and injury are discussed in relation to their associated host immune pathways. CAP epidemiology is considered, with a focus on Staphylococcus aureus and Streptococcus pneumoniae as primary pathogens. Bacterial factors involved in nasal colonization and subsequent virulence are illuminated. A particular emphasis is placed on bacterial pore-forming toxins, host cell death, and inflammasome activation. Identified host-pathogen interactions are then examined by linking pathogen factors to aberrant host response pathways in the context of acute lung injury in both primary and secondary infection. While much is known regarding bacterial virulence and host immune responses, CAP management is still limited to mostly supportive care. It is likely that improvements in therapy will be derived from combinatorial targeting of both pathogen virulence factors and host immunomodulation.

Influenza A is a highly contagious respiratory virus that causes seasonal epidemics and occasional worldwide pandemics. The primary cause of influenza-related mortality is bacterial super-infection. There are numerous mechanisms by which preceding influenza infection attenuates host defense, allowing for increased susceptibility to bacterial pneumonia. Herein, we demonstrate that influenza inhibits Staphylococcus aureus-induced production of IL-33. Restoration of IL-33 during influenza A and MRSA super-infection enhanced bacterial clearance and improved mortality. ILC2s and alternatively activated macrophages are not required for IL-33 mediated protection during super-infection. We show that IL-33 treatment resulted in neutrophil recruitment to the lung, associated with improved bacterial clearance. These findings identify a novel role for IL-33 in anti-bacterial host defense at the mucosal barrier.

Secondary bacterial pneumonia is a significant complication of severe influenza infection and Staphylococcus aureus and Streptococcus pneumoniae are the primary pathogens of interest. IL-22 promotes S. aureus and S. pneumoniae host defense in the lung through epithelial integrity and induction of antimicrobial peptides and is inhibited by the soluble decoy receptor IL-22 binding protein (IL-22BP). Little is known about the effect of the IL-22/IL-22BP regulatory pathway on lung infection, and it has not been studied in the setting of super-infection. We exposed wild-type and IL-22BP −/− mice to influenza A/PR/8/34 for six days prior to infection with S. aureus (USA300) S. pneumoniae . Super-infected IL-22BP −/− mice had decreased bacterial burden and improved survival compared to controls. IL-22BP −/− mice exhibited decreased inflammation, increased lipocalin 2 expression, and deletion of IL-22BP was associated with preserved epithelial barrier function with evidence of improved tight junction stability. Human bronchial epithelial cells treated with IL-22Fc showed evidence of improved tight junctions compared to untreated cells. This study revealed that IL-22BP −/− mice are protected during influenza, bacterial super-infection, suggesting that IL-22BP has a pro-inflammatory role and impairs epithelial barrier function likely through interaction with IL-22

Asthma is a highly prevalent, chronic respiratory disease that impacts millions of people worldwide and causes thousands of deaths every year. Asthmatics display different phenotypes with distinct genetic components, environmental causes, and immunopathologic signatures, and are broadly characterized into type 2-high or type 2-low (non-type 2) endotypes by linking clinical characteristics, steroid responsiveness, and molecular pathways. Regardless of asthma severity and adequate disease management, patients may experience acute exacerbations of symptoms and a loss of disease control, often triggered by respiratory infections. The interferon (IFN) family represents a group of cytokines that play a central role in the protection against and exacerbation of various infections and pathologies, including asthma. Type I and III IFNs in particular play an indispensable role in the host immune system to fight off pathogens, which seems to be altered in both pediatric and adult asthmatics. Impaired IFN production leaves asthmatics susceptible to infection and with uncontrolled type 2 immunity, promotes airway hyperresponsiveness (AHR), and inflammation which can lead to asthma exacerbations. However, IFN deficiency is not observed in all asthmatics, and alterations in IFN expression may be independent of type 2 immunity. In this review, we discuss the link between type I and III IFNs and asthma both in general and in specific contexts, including during viral infection, co-infection, and bacterial/fungal infection. We also highlight several studies which examine the potential role for type I and III IFNs as asthma-related therapies.

Influenza kills 30,000 to 40,000 people each year in the United States and causes 10 times as many hospitalizations. A common complication of influenza is bacterial superinfection, which exacerbates morbidity and mortality from the viral illness. Recently, methicillin-resistant Staphylococcus aureus (MRSA) has emerged as the dominant pathogen found in bacterial superinfection, with Streptococcus pneumoniae a close second. However, clinicians have few tools to treat bacterial superinfection. Current therapy for influenza/bacterial superinfection consists of treating the underlying influenza infection and adding various antibiotics, which are increasingly rendered ineffective by rising bacterial multidrug resistance. Several groups have recently proposed the use of the antiviral cytokine interferon lambda (IFN-) as a therapeutic for influenza, as administration of pegylated IFN-improves lung function and survival during influenza by reducing the overabundance of neutrophils in the lung. However, our data suggest that therapeutic IFNimpairs bacterial clearance during influenza superinfection. Specifically, mice treated with an adenoviral vector to overexpress IFNduring influenza infection exhibited increased bacterial burdens upon superinfection with either MRSA or S. pneumoniae. Surprisingly, adhesion molecule expression, antimicrobial peptide production, and reactive oxygen species activity were not altered by IFNtreatment. However, neutrophil uptake of MRSA and S. pneumoniae was significantly reduced upon IFN-treatment during influenza superinfection in vivo. Together, these data support the theory that IFN-decreases neutrophil motility and function in the influenza-infected lung, which increases the bacterial burden during superinfection. Thus, we believe that caution should be exercised in the possible future use of IFNas therapy for influenza.