Impact of interferon λ signaling on lung macrophage function and type 17 immunity during bacterial super-infection following influenza
NIH
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Abstract Lung diseases and syndromes caused by respiratory pathogens represent a leading cause of death worldwide. Each year, influenza infections result in a significant number of fatalities, a majority of which are complicated by secondary bacterial super-infection. Primary influenza infection has been shown to increase susceptibility to secondary methicillin-resistant Staphylococcus aureus (MRSA) infection by altering the pulmonary host immune response and damaging the lung epithelial barrier, leading to increased morbidity and mortality. Macrophages, both lung-resident and those recruited to the lung, are important in super-infection resolution as they engulf, degrade, and present bacterial antigen to adaptive immune cells, ultimately leading to activation of type 17 cells, which promote pathogen clearance. While the role of interferon-(IFN)α/β during super-infection has been well characterized, type III IFNs have not been as extensively studied within the context of the lung. Data shows that IFNα/β are involved in type 17 attenuation after primary influenza infection, which may indicate that IFNλ exhibits similar inhibitory functions due to overlapping signaling pathways, although the potential for unique functions on lung cells is unresolved. Our lab has preliminary data suggesting that administration of exogenous IFNλ during super-infection reduces bacterial uptake by neutrophils and monocyte-derived cells, but the specific cell subsets impacted are unknown. I hypothesize that lung-resident macrophages are sensitive to IFNλ and that IFNλ signaling impairs phagocytosis and the type 17 immune response during super-infection. In the proposed studies, I will determine which myeloid subsets express the IFNλ receptor (IFNLR1) and identify how intact or disrupted IFNλ signaling broadly impacts lung injury and resolution after infection. More specifically, these experiments will determine how IFNλ impacts MRSA uptake and the initiation of a type 17 immune response during super- infection. IFNλ administration has been considered for therapeutic potential, and the outcomes of this proposal will shed light on potential caveats to the use of IFNλ as a possible treatment method during super-infection. Further, demonstration of the effects of IFNλ on myeloid cells will potentially be applicable to several other settings where an antiviral interferon response is observed. Project Narrative A severe complication of influenza infection is secondary Staphylococcus aureus, and previous data has shown that type I interferons produced during influenza infection result in a defective bacterial immune response. Type III interferons are a more recently discovered family of interferons that share signaling pathways with type I interferons. This project will determine the role of type III interferons in impairment of the immune response against secondary bacterial infection by decreasing lung macrophage function and subsequent type 17 immune induction.
Training, Individual