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Query: UMLS:C0032285 (pneumonia)
 54,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pneumococcus has been shown to bind to epithelial cells of the nasopharynx and lung, and to endothelial cells of the peripheral vasculature. To characterize bacterial elements required for attachment to these cell types, a library of genetically altered pneumococci with defects in exported proteins was screened for the loss of attachment to glycoconjugates representative of the nasopharyngeal cell receptor, type II lung cells (LC) and human endothelial cells (EC). A mutant was identified which showed a greater than 70% loss in the ability to attach to all cell types. This mutant also showed decreased adherence to the glycoconjugates containing the terminal sugar residues GalNAcbeta1-3Gal, GalNAcbeta1-4Gal and the carbohydrate GlcNAc, which are proposed components of the pneumococcal receptors specific to the surfaces of LC and EC. Analysis of the locus altered in this mutant revealed a gene, spxB, that encodes a member of the family of bacterial pyruvate oxidases which decarboxylates pyruvate to acetyl phosphate plus H2O2 and CO2. This mutant produced decreased concentrations of H2O2 and failed to grow aerobically in a chemically defined medium, unless supplemented with acetate which presumably restores acetyl phosphate levels by the action of acetate kinase, further suggesting that spxB encodes a pyruvate oxidase. The addition of acetate to the growth medium restored the adherence properties of the mutant indicating a link between the enzyme and the expression of bacterial adhesins. A defect in spxB corresponded to impaired virulence of the mutant in vivo. Compared to the parent strain, an spxB mutant showed reduced virulence in animal models for nasopharyngeal colonization, pneumonia, and sepsis. We propose that a mutation in spxB leads to down-regulation of the multiple adhesive properties of pneumococcus which, in turn, may correlate to diminished virulence in vivo.
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PMID:Pyruvate oxidase, as a determinant of virulence in Streptococcus pneumoniae. 882 Jun 50

Streptococcus pneumoniae is a leading cause of pneumonia and one of the most common causes of death globally. The impact of S. pneumoniae on host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show that S. pneumoniae induces toxic DNA double-strand breaks (DSBs) in human alveolar epithelial cells, as indicated by ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of histone H2AX and colocalization with p53-binding protein (53BP1). Furthermore, results show that DNA damage occurs in a bacterial contact-independent fashion and that Streptococcus pyruvate oxidase (SpxB), which enables synthesis of H2O2, plays a critical role in inducing DSBs. The extent of DNA damage correlates with the extent of apoptosis, and DNA damage precedes apoptosis, which is consistent with the time required for execution of apoptosis. Furthermore, addition of catalase, which neutralizes H2O2, greatly suppresses S. pneumoniae-induced DNA damage and apoptosis. Importantly, S. pneumoniae induces DSBs in the lungs of animals with acute pneumonia, and H2O2 production by S. pneumoniae in vivo contributes to its genotoxicity and virulence. One of the major DSBs repair pathways is nonhomologous end joining for which Ku70/80 is essential for repair. We find that deficiency of Ku80 causes an increase in the levels of DSBs and apoptosis, underscoring the importance of DNA repair in preventing S. pneumoniae-induced genotoxicity. Taken together, this study shows that S. pneumoniae-induced damage to the host cell genome exacerbates its toxicity and pathogenesis, making DNA repair a potentially important susceptibility factor in people who suffer from pneumonia.
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PMID:Streptococcus pneumoniae secretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells. 2608 Apr 6

Streptococcus pneumoniae (the pneumococcus) is the leading cause of community-acquired pneumonia and is now recognized to be a direct contributor to adverse acute cardiac events. During invasive pneumococcal disease, S. pneumoniae can gain access to the myocardium, kill cardiomyocytes, and form bacterium-filled "microlesions" causing considerable acute and long-lasting cardiac damage. While the molecular mechanisms responsible for bacterial translocation into the heart have been elucidated, the initial interactions of heart-invaded S. pneumoniae with cardiomyocytes remain unclear. In this study, we used a model of low multiplicity of S. pneumoniae infection with HL-1 mouse cardiomyocytes to investigate these early events. Using adhesion/invasion assays and immunofluorescent and transmission electron microscopy, we showed that S. pneumoniae rapidly adhered to and invaded cardiomyocytes. What is more, pneumococci existed as intravacuolar bacteria or escaped into the cytoplasm. Pulse-chase assays with BrdU confirmed intracellular replication of pneumococci within HL-1 cells. Using endocytosis inhibitors, bacterial isogenic mutants, and neutralizing antibodies against host proteins recognized by S. pneumoniae adhesins, we showed that S. pneumoniae uptake by cardiomyocytes is not through the well-studied canonical interactions identified for vascular endothelial cells. Indeed, S. pneumoniae invasion of HL-1 cells occurred through clathrin-mediated endocytosis (CME) and independently of choline binding protein A (CbpA)/laminin receptor, CbpA/polymeric immunoglobulin receptor, or cell wall phosphorylcholine/platelet-activating factor receptor. Subsequently, we determined that pneumolysin and streptococcal pyruvate oxidase-derived H2O2 production were required for cardiomyocyte killing. Finally, we showed that this cytotoxicity could be abrogated using CME inhibitors or antioxidants, attesting to intracellular replication of S. pneumoniae as a key first step in pneumococcal pathogenesis within the heart.
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PMID:Cell Invasion and Pyruvate Oxidase-Derived H2O2 Are Critical for Streptococcus pneumoniae-Mediated Cardiomyocyte Killing. 2906 7

Streptococcus pneumoniae (the pneumococcus) is a human respiratory tract pathogen and a major cause of morbidity and mortality globally. Although the pneumococcus is a commensal bacterium that colonizes the nasopharynx, it also causes lethal diseases such as meningitis, sepsis, and pneumonia, especially in immunocompromised patients, in the elderly, and in young children. Due to the acquisition of antibiotic resistance and the emergence of nonvaccine serotypes, the pneumococcus has been classified as one of the priority pathogens for which new antibacterials are urgently required by the World Health Organization, 2017. Understanding molecular mechanisms behind the pathogenesis of pneumococcal infections and bacterial interactions within the host is crucial to developing novel therapeutics. Previously considered to be an extracellular pathogen, it is becoming evident that pneumococci may also occasionally establish intracellular niches within the body to escape immune surveillance and spread within the host. Intracellular survival within host cells also enables pneumococci to resist many antibiotics. Within the host cell, the bacteria exist in unique vacuoles, thereby avoiding degradation by the acidic lysosomes, and modulate the expression of its virulence genes to adapt to the intracellular environment. To invade and survive intracellularly, the pneumococcus utilizes a combination of virulence factors such as pneumolysin (PLY), pneumococcal surface protein A (PspA), pneumococcal adhesion and virulence protein B (PavB), the pilus-1 adhesin RrgA, pyruvate oxidase (SpxB), and metalloprotease (ZmpB). In this review, we discuss recent findings showing the intracellular persistence of Streptococcus pneumoniae and its underlying mechanisms.
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PMID:Emerging concepts in the pathogenesis of the Streptococcus pneumoniae: From nasopharyngeal colonizer to intracellular pathogen. 3125 47