16 research outputs found
Genetic variability of innate immunity impacts human susceptibility to fungal diseases.
AbstractFungi are a major threat in immunocompromised patients. Despite presenting similar degrees of immunosuppression, not all individuals at-risk ultimately develop fungal diseases. The traditional view of immune suppression as a key risk factor for susceptibility to fungal infections needs to be accommodated within new conceptual advances on host immunity and its relationship to fungal disease. The critical role of the immune system emphasizes the contribution of host genetic polymorphisms to fungal disease susceptibility. This review highlights the present knowledge on innate immunity genetics that associates with susceptibility to fungal diseases
Plasminogen Alleles Influence Susceptibility to Invasive Aspergillosis
Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection
Transcriptomic signatures differentiate survival from fatal outcomes in humans infected with Ebola virus
Survival after Bronchiolitis Obliterans Syndrome among Bilateral Lung Transplant Recipients
Rationale: Despite the importance of bronchiolitis obliterans syndrome (BOS) in lung transplantation, little is known regarding the factors that influence survival after the onset of this condition, particularly among bilateral transplant recipients
Counteracting Signaling Activities in Lipid Rafts Associated with the Invasion of Lung Epithelial Cells by Pseudomonas aeruginosa*
Pseudomonas aeruginosa has the capacity to invade lung epithelial
cells by co-opting the intrinsic endocytic properties of lipid rafts, which
are rich in cholesterol, sphingolipids, and proteins, such as caveolin-1 and
-2. We compared intratracheal Pseudomonas infection in wild type and
caveolin-deficient mice to investigate the role of caveolin proteins in the
pathogenesis of Pseudomonas pneumonia. Unlike wild type mice, which
succumb to pneumonia, caveolin-deficient mice are resistant to
Pseudomonas. We observed that Pseudomonas invasion of lung
epithelial cells is dependent on caveolin-2 but not caveolin-1.
Phosphorylation of caveolin-2 by Src family kinases is an essential event for
Pseudomonas invasion. Our studies also reveal the existence of a
distinct signaling mechanism in lung epithelial cells mediated by
COOH-terminal Src kinase (Csk) that negatively regulates Pseudomonas
invasion. Csk migrates to lipid raft domains, where it decreases
phosphorylation of caveolin-2 by inactivating c-Src. Whereas
Pseudomonas co-opts the endocytic properties of caveolin-2 for
invasion, there also exists in these cells an intrinsic Csk-dependent cellular
defense mechanism aimed at impairing this activity. The success of
Pseudomonas in co-opting lipid raft-mediated endocytosis to invade
lung epithelial cells may depend on the relative strengths of these
counteracting signaling activities