Asthma induced exacerbation of bacterial pneumonia.

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.Open Acces

Bacterial superinfection following lung inflammatory disorders.

The lung environment is designed to prevent innate responses to harmless commensal microorganisms and environmental antigens. Features of an intact respiratory epithelium are critical to this process. A damaged or altered lung epithelial surface will therefore remove or alter the suppressive signals delivered to local innate immune cells, and inflammation ensues. Timely resolution of inflammation is important to prevent bystander tissue damage. However, if resolving pathways themselves are prolonged or repeated, they too can cause undesirable consequences, including bacterial superinfections, which we discuss here. </jats:p

Tir Triggers Expression of CXCL1 in Enterocytes and Neutrophil Recruitment during Citrobacter rodentium Infection.

The hallmarks of enteropathogenic Escherichia coli (EPEC) infection are formation of attaching and effacing (A/E) lesions on mucosal surfaces and actin-rich pedestals on cultured cells, both of which are dependent on the type III secretion system effector Tir. Following translocation into cultured cells and clustering by intimin, Tir Y474 is phosphorylated, leading to recruitment of Nck, activation of N-WASP, and actin polymerization via the Arp2/3 complex. A secondary, weak, actin polymerization pathway is triggered via an NPY motif (Y454). Importantly, Y454 and Y474 play no role in A/E lesion formation on mucosal surfaces following infection with the EPEC-like mouse pathogen Citrobacter rodentium. In this study, we investigated the roles of Tir segments located upstream of Y451 and downstream of Y471 in C. rodentium colonization and A/E lesion formation. We also tested the role that Tir residues Y451 and Y471 play in host immune responses to C. rodentium infection. We found that deletion of amino acids 382 to 462 or 478 to 547 had no impact on the ability of Tir to mediate A/E lesion formation, although deletion of amino acids 478 to 547 affected Tir translocation. Examination of enterocytes isolated from infected mice revealed that a C. rodentium strain expressing Tir_Y451A/Y471A recruited significantly fewer neutrophils to the colon and triggered less colonic hyperplasia on day 14 postinfection than the wild-type strain. Consistently, enterocytes isolated from mice infected with C. rodentium expressing Tir_Y451A/Y471A expressed significantly less CXCL1. These result show that Tir-induced actin remodeling plays a direct role in modulation of immune responses to C. rodentium infection