ABSTRACT
Legionella pneumophila (Lp) is a flagellated, intracellular bacterium that can cause Legionnaires' disease (LD). Lp activates multiple innate immune receptors, and TOLLIP dampens MyD88-dependent signaling and may influence susceptibility to LD. We evaluated the effect of TOLLIP on innate immunity, pneumonia severity, and LD susceptibility in mouse lungs and human populations. To accomplish this, we evaluated the effect of TOLLIP on lung-specific Lp control and immune response and associated a common functional TOLLIP variant with Lp-induced innate immune responses and LD susceptibility in humans. After aerosol Lp infection, Tollip-/- mice demonstrated significantly fewer bacterial colony-forming unit and increased cytokine responses from BAL fluid. Tollip-/- macrophages also suppressed intracellular Lp replication in a flagellin-independent manner. The presence of a previously characterized, functionally active SNP associated with decreased TOLLIP mRNA transcript in monocytes was associated with increased TNF and IL-6 secretion after Lp stimulation of PBMC ex vivo. This genotype was separately associated with decreased LD susceptibility (309 controls, 88 cases, p = 0.008, OR 0.36, 95% CI 0.16-0.76) in a candidate gene association study. These results suggest that TOLLIP decreases lung-specific TLR responses to increase LD susceptibility in human populations. Better understanding of TOLLIP may lead to novel immunomodulatory therapies.
Subject(s)
Intracellular Signaling Peptides and Proteins/deficiency , Legionella pneumophila/pathogenicity , Legionnaires' Disease/metabolism , Lung/metabolism , Adult , Aged , Animals , Bacterial Load , Case-Control Studies , Cells, Cultured , Cytokines/metabolism , Disease Models, Animal , Female , Host-Pathogen Interactions , Humans , Immunity, Innate , Inflammation Mediators/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Legionella pneumophila/growth & development , Legionella pneumophila/immunology , Legionnaires' Disease/genetics , Legionnaires' Disease/immunology , Legionnaires' Disease/microbiology , Lung/immunology , Lung/microbiology , Macrophages/immunology , Macrophages/metabolism , Macrophages/microbiology , Male , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Severity of Illness Index , Signal TransductionABSTRACT
Ordered two-dimensional (2D) lattices were formed by assembling silica-coated solid and segmented Au nanowires between coplanar electrodes using alternating current (ac) electric fields. Dielectrophoretic forces from the ac field concentrated wires between the electrodes, with their long axis aligned parallel to the field lines. After reaching a sufficient particle density, field-induced dipolar interactions resulted in the assembly of dense 2D lattices that spanned the electrodes, a distance of at least ten wire lengths. The ends of neighboring Au wires or segments overlapped a fraction of their length to form lattice structures with a "running bond" brickwork-like pattern. The observed lattice structures were tunable in three distinct ways: (1) particle segmentation pattern, which fixed the lattice periodicity for a given field condition; (2) ac frequency, which varied lattice periodicity in real time; and (3) switching the field on/off, which converted between lattice and smectic particle organizations. Electric field simulations were performed to understand how the observed lattice periodicity depends on the assembly conditions and particle segmentation. Directed self-assembly of well-ordered 2D metallic nanowire lattices that can be designed by Au striping pattern and reconfigured by changes in field conditions could enable new types of switchable optical or electronic devices.
