Asthma induced exacerbation of bacterial pneumonia.

Abstract

Asthma and bacterial pneumonias are major causes of human mortality and morbidity throughout the world. To date many studies have investigated the possibility that bacteria exacerbate asthma but only a handful consider that asthma may cause bacterial infections. Recent clinical evidence suggests that bacterial infections cause serious complications in patients with asthma and that asthmatics show a 2-fold increased risk of invasive pneumococcal disease. This thesis examines the molecular mechanisms causing susceptibility of house dust mite (HDM) exposed lungs to bacterial infection. The main finding of this thesis is that HDM-induced allergic airways disease increases susceptibility to Streptococcus pneumoniae infection. Furthermore, the molecular pathways leading to the production of neutrophil chemoattractants in the lung are compromised and that despite the complexity of anti-bacterial pathways that are disrupted, the re-introduction of a single chemokine to the lungs with allergic airway disease enables clearance of S. pneumoniae that would otherwise prove fatal. However, a reduction in HDM-induced eosinophilia seen in ST2 deficient mice does not restore anti-bacterial immunity. This deficit in anti-bacterial immunity in HDM exposed lungs is associated with a change in resident alveolar macrophages into an alternatively activated phenotype, characterised by high mRNA and protein levels of RELMα, Ym1 and Arg1. These altered alveolar macrophages produce considerably less TNFα in response to Toll-Like Receptor (TLR) stimulation that is not a result of reduced TLR mRNA levels but due to an upregulation of TLR negative regulators particularly A20. A20 targets TRAF-6 that is found upstream of NF-κB activation. To prove a causal link naïve alveolar macrophages were transferred into allergic lungs prior to bacterial infection; such lungs handled the infection better confirming that alveolar macrophages are important in initiating the anti-bacterial response. Overall our findings highlight a change in specific innate immune pathways in the allergic lung that participate in susceptibility to bacterial pneumonia.