scholarly journals Impact of theglpQ2Gene on Virulence in a Streptococcus pneumoniae Serotype 19A Sequence Type 320 Strain

2014 ◽  
Vol 83 (2) ◽  
pp. 682-692 ◽  
Author(s):  
Yi-Ping Chuang ◽  
Zih-Rong Peng ◽  
Shun-Fu Tseng ◽  
Yu-Chun Lin ◽  
Huey-Kang Sytwu ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Parent Strain ◽  
Severe Pneumonia ◽  
Exponential Phase ◽  
Sequence Type ◽  
Infection Model ◽  
Respiratory Pathogens ◽  
Content Type ◽  
Human Lung Epithelial Cell ◽  
Lung Colonization

Glycerophosphodiester phosphodiesterase (GlpQ) metabolizes glycerophosphorylcholine from the lung epithelium to produce free choline, which is transformed into phosphorylcholine and presented on the surfaces of many respiratory pathogens. Two orthologs ofglpQgenes are found inStreptococcus pneumoniae:glpQ, with a membrane motif, is widespread in pneumococci, whereasglpQ2, which shares high similarity withglpQinHaemophilus influenzaeandMycoplasma pneumoniae, is present only inS. pneumoniaeserotype 3, 6B, 19A, and 19F strains. Recently, serotype 19A has emerged as an epidemiological etiology associated with invasive pneumococcal diseases. Thus, we investigated the pathophysiological role ofglpQ2in a serotype 19A sequence type 320 (19AST320) strain, which was the prevalent sequence type in 19A associated with severe pneumonia and invasive pneumococcal disease in pediatric patients. Mutations inglpQ2reduced phosphorylcholine expression and the anchorage of choline-binding proteins to the pneumococcal surface during the exponential phase, where the mutants exhibited reduced autolysis and lower natural transformation abilities than the parent strain. The deletion ofglpQ2also decreased the adherence and cytotoxicity to human lung epithelial cell lines, whereas these functions were indistinguishable from those of the wild type in complementation strains. In a murine respiratory tract infection model,glpQ2was important for nasopharynx and lung colonization. Furthermore, infection with aglpQ2mutant decreased the severity of pneumonia compared with the parent strain, andglpQ2gene complementation restored the inflammation level. Therefore,glpQ2enhances surface phosphorylcholine expression inS. pneumoniae19AST320 during the exponential phase, which contributes to the severity of pneumonia by promoting adherence and host cell cytotoxicity.

scholarly journals Nosocomial Outbreak of Drug-Resistant Streptococcus pneumoniae Serotype 9V in an Adult Respiratory Medicine Ward

2016 ◽  
Vol 55 (3) ◽  
pp. 776-782 ◽  
Author(s):  
Elita Jauneikaite ◽  
Zareena Khan-Orakzai ◽  
Georgia Kapatai ◽  
Susannah Bloch ◽  
Julie Singleton ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Lower Respiratory Tract ◽  
Sequence Type ◽  
Resistance Pattern ◽  
Whole Genome ◽  
Drug Resistant ◽  
Nosocomial Outbreak ◽  
Content Type ◽  
Rapid Transmission ◽  
Case Presentations

ABSTRACT Streptococcus pneumoniae infections arising in hospitalized patients are often assumed to be sporadic and linked to community acquisition. Here, whole-genome sequencing was used to demonstrate nosocomial acquisition of antimicrobial-resistant sequence type 156 (ST156) serotype 9V S. pneumoniae in 3 respiratory patients that resulted in two bacteremias and one lower respiratory tract infection. Two of the cases arose in patients who had recently been discharged from the hospital and were readmitted from the community. Nosocomial spread was suspected solely because of the highly unusual resistance pattern and case presentations within 24 h of one another. The outbreak highlights the potential for rapid transmission and the short incubation period in the respiratory ward setting.

scholarly journals Complete Genome Sequence of a Sequence Type 4846 Streptococcus pneumoniae Serotype 12F Strain Isolated from a Meningitis Case in Japan

2019 ◽  
Vol 8 (11) ◽  
Author(s):  
Bin Chang ◽  
Masatomo Morita ◽  
Ken-ichi Lee ◽  
Makoto Ohnishi
Keyword(s):  
Streptococcus Pneumoniae ◽  
Invasive Pneumococcal Disease ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
Pneumococcal Disease ◽  
Sequence Type ◽  
Content Type ◽  
Meningitis Case

Streptococcus pneumoniae serotype 12F rarely colonizes the nasopharynx but commonly causes invasive pneumococcal disease. Here, we report the complete genome sequence of a sequence type 4846 (ST4846) S. pneumoniae serotype 12F strain isolated from a cluster of invasive pneumococcal disease patients in Japan.

scholarly journals Complete Genome Sequence of GD1108, a Moderate-Virulence Strain of Human-Associated ST398 Methicillin-Susceptible Staphylococcus aureus

2019 ◽  
Vol 8 (28) ◽  
Author(s):  
Jo-Ann McClure ◽  
Steven M. Shideler ◽  
Kunyan Zhang
Keyword(s):  
Staphylococcus Aureus ◽  
Caenorhabditis Elegans ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
Sequence Type ◽  
Infection Model ◽  
Content Type ◽  
Severe Infections

Staphylococcus aureus multilocus sequence type 398 (ST398) is responsible for an increasing number of severe infections in humans. There are no reports detailing if all ST398 strains are equally virulent. We present the genome sequence of the moderate-virulence ST398 methicillin-susceptible Staphylococcus aureus strain GD1108, determined in a Caenorhabditis elegans infection model, to reveal the ST398 sublineage virulence.

scholarly journals A Novel Zinc Binding System, ZevAB, Is Critical for Survival of Nontypeable Haemophilus influenzae in a Murine Lung Infection Model

2011 ◽  
Vol 79 (8) ◽  
pp. 3366-3376 ◽  
Author(s):  
Charles V. Rosadini ◽  
Jeffrey D. Gawronski ◽  
Daniel Raimunda ◽  
José M. Argüello ◽  
Brian J. Akerley
Keyword(s):  
Haemophilus Influenzae ◽  
Respiratory Infections ◽  
Bacterial Pathogen ◽  
Lung Infection ◽  
Lung Model ◽  
Mouse Lung ◽  
Infection Model ◽  
Nontypeable Haemophilus Influenzae ◽  
Content Type ◽  
Lung Colonization

ABSTRACTNontypeableHaemophilus influenzae(NTHI) is a Gram-negative bacterial pathogen that causes upper and lower respiratory infections. Factors required for pulmonary infection by NTHI are not well understood. Previously, using high-throughput insertion tracking by deep sequencing (HITS), putative lung colonization factors were identified. Also, previous research indicates that secreted disulfide-dependent factors are important for virulence ofH. influenzae. In the present study, HITS data were compared with an informatics-based list of putative substrates of the periplasmic oxidoreductase DsbA to find and characterize secreted virulence factors. This analysis resulted in identification of the “zinc bindingessential forvirulence” (zev) locus consisting ofzevA(HI1249) andzevB(HI1248). NTHI mutants ofzevAandzevBgrew normally in rich medium but were defective for colonization in a mouse lung model. Mutants also exhibited severe growth defects in medium containing EDTA and were rescued by supplementation with zinc. Additionally, purified recombinant ZevA was found to bind to zinc with high affinity. Together, these data demonstrate thatzevABis a novel virulence factor important for zinc utilization ofH. influenzaeunder conditions where zinc is limiting. Furthermore, evidence presented here suggests that zinc limitation is likely an important mechanism for host defense against pathogens during lung infection.

scholarly journals In VivoPharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

2016 ◽  
Vol 60 (8) ◽  
pp. 4764-4769 ◽  
Author(s):  
Alexander J. Lepak ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Single Dose ◽  
Streptococcus Pneumoniae ◽  
Klebsiella Pneumoniae ◽  
Dose Response ◽  
Lung Infection ◽  
Infection Model ◽  
Content Type ◽  
Murine Lung

ABSTRACTDelafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection model forStaphylococcus aureus,Streptococcus pneumoniae, andKlebsiella pneumoniae. Four isolates of each species were utilized forin vivostudies: forS. aureus, one methicillin-susceptible and three methicillin-resistant isolates;S. pneumoniae, two penicillin-susceptible and two penicillin-resistant isolates;K. pneumoniae, one wild-type and three extended-spectrum beta-lactamase-producing isolates. MICs were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies, and drug dosing was by the subcutaneous route. Single-dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40, and 160 mg/kg. Forin vivostudies, 4-fold-increasing doses of delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to infected mice. Treatment outcome was measured by determining organism burden in the lung (CFU counts) at the end of each experiment (24 h). The Hill equation for maximum effect (Emax) was used to model the dose-response data. The magnitude of the PK/PD index, the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC), associated with net stasis and 1-log kill endpoints was determined in the lung model for all isolates. MICs ranged from 0.004 to 1 mg/liter. Single-dose PK parameter ranges include the following: for maximum concentration of drug in serum (Cmax), 2 to 70.7 mg/liter; AUC from 0 h to infinity (AUC0–∞), 2.8 to 152 mg · h/liter; half-life (t1/2), 0.7 to 1 h. At the start of therapy mice had 6.3 ± 0.09 log10CFU/lung. In control mice the organism burden increased 2.1 ± 0.44 log10CFU/lung over the study period. There was a relatively steep dose-response relationship observed with escalating doses of delafloxacin. Maximal organism reductions ranged from 2 log10to more than 4 log10. The median free-drug AUC/MIC magnitude associated with net stasis for each species group was 1.45, 0.56, and 40.3 forS. aureus,S. pneumoniae, andK. pneumoniae, respectively. AUC/MIC targets for the 1-log kill endpoint were 2- to 5-fold higher. Delafloxacin demonstratedin vitroandin vivopotency against a diverse group of pathogens, including those with phenotypic drug resistance to other classes. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints for delafloxacin for the treatment of lower respiratory tract infections involving these pathogens.

scholarly journals In VivoPharmacodynamic Target Investigation of Two Bacterial Topoisomerase Inhibitors, ACT-387042 and ACT-292706, in the Neutropenic Murine Thigh Model against Streptococcus pneumoniae and Staphylococcus aureus

2016 ◽  
Vol 60 (6) ◽  
pp. 3626-3632 ◽  
Author(s):  
A. J. Lepak ◽  
P. Seiler ◽  
J. P. Surivet ◽  
D. Ritz ◽  
C. Kohl ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Dose Range ◽  
Free Drug ◽  
Infection Model ◽  
Topoisomerase Inhibitors ◽  
Time Curve ◽  
Content Type ◽  
Phenotypic Resistance

ACT-387042 and ACT-292706 are two novel bacterial topoisomerase inhibitors with broad-spectrum activity against Gram-positive and -negative bacteria, including methicillin-resistantStaphylococcus aureusand penicillin- and fluoroquinolone-resistantStreptococcus pneumoniae. We used the neutropenic murine thigh infection model to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of these investigational compounds against a group of 10S. aureusandS. pneumoniaeisolates with phenotypic resistance to beta-lactams and fluoroquinolones. Thein vitroactivities of the two compounds were very similar (MIC range, 0.03 to 0.125 mg/liter). Plasma pharmacokinetics were determined for each compound by using four escalating doses administered by the subcutaneous route. In treatment studies, mice had 107.4to 108CFU/thigh at the start of therapy with ACT-387042 and 106.7to 108.3CFU/thigh at the start of therapy with ACT-292706. A dose-response relationship was observed with all isolates over the dose range. Maximal kill approached 3 to 4 log10CFU/thigh compared to the burden at the start of therapy for the highest doses examined. There was a strong relationship between the PK/PD index AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) and therapeutic efficacy in the model (R2, 0.63 to 0.82). The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-387042 againstS. aureusandS. pneumoniaewere 43 and 10, respectively. The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-292706 againstS. aureusandS. pneumoniaewere 69 and 25, respectively. The stasis PD targets were significantly lower forS. pneumoniae(P< 0.05) for both compounds. The 1-log-kill AUC/MIC ratio targets were ∼2- to 4-fold higher than stasis targets. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy. These results should be helpful in the design of clinical trials for topoisomerase inhibitors.

scholarly journals Complete Genome Sequences of Streptococcus pneumoniae Strains HU-OH (Serotype 3, Sequence Type 183 [ST183]), NU83127 (Serotype 4, ST246), and ATCC 49619 (Serotype 19F, ST1203)

2019 ◽  
Vol 8 (9) ◽  
Author(s):  
Kentaro Nagaoka ◽  
Satoshi Konno ◽  
Kazunori Murase ◽  
Taisei Kikuchi ◽  
Yoshitomo Morinaga ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Bacterial Meningitis ◽  
Respiratory Tract ◽  
Complete Genome ◽  
Sequence Type ◽  
Pathogenic Bacterium ◽  
Genome Sequences ◽  
Content Type ◽  
Circular Genome ◽  
Sequence Types

Streptococcus pneumoniae is a pathogenic bacterium frequently found in the respiratory tract of humans and commonly causes pneumonia and bacterial meningitis. Here, the complete circular genome sequences of three S. pneumoniae strains with different serotypes and sequence types have been reported.

scholarly journals Toll-Like Receptor 4 Agonistic Antibody Promotes Innate Immunity against Severe Pneumonia Induced by Coinfection with Influenza Virus and Streptococcus pneumoniae

2013 ◽  
Vol 20 (7) ◽  
pp. 977-985 ◽  
Author(s):  
Akitaka Tanaka ◽  
Shigeki Nakamura ◽  
Masafumi Seki ◽  
Kenji Fukudome ◽  
Naoki Iwanaga ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Influenza Virus ◽  
Streptococcus Pneumoniae ◽  
Pneumococcal Pneumonia ◽  
Survival Rates ◽  
Severe Pneumonia ◽  
Histopathological Study ◽  
Toll Like Receptor ◽  
Content Type ◽  
Monocyte Chemoattractant Protein 1

ABSTRACTCoinfection with bacteria is a major cause of mortality during influenza epidemics. Recently, Toll-like receptor (TLR) agonists were shown to have immunomodulatory functions. In the present study, we investigated the effectiveness and mechanisms of the new TLR4 agonistic monoclonal antibody UT12 against secondary pneumococcal pneumonia induced by coinfection with influenza virus in a mouse model. Mice were intranasally inoculated withStreptococcus pneumoniae2 days after influenza virus inoculation. UT12 was intraperitoneally administered 2 h before each inoculation. Survival rates were significantly increased and body weight loss was significantly decreased by UT12 administration. Additionally, the production of inflammatory mediators was significantly suppressed by the administration of UT12. In a histopathological study, pneumonia in UT12-treated mice was very mild compared to that in control mice. UT12 increased antimicrobial defense through the acceleration of macrophage recruitment into the lower respiratory tract induced by c-Jun N-terminal kinase (JNK) and nuclear factor kappaB (NF-κB) pathway-dependent monocyte chemoattractant protein 1 (MCP-1) production. Collectively, these findings indicate that UT12 promoted pulmonary innate immunity and may reduce the severity of severe pneumonia induced by coinfection with influenza virus andS. pneumoniae. This immunomodulatory effect of UT12 improves the prognosis of secondary pneumococcal pneumonia and makes UT12 an attractive candidate for treating severe infectious diseases.

scholarly journals In Vivo Pharmacodynamic Evaluation of Omadacycline (PTK 0796) against Streptococcus pneumoniae in the Murine Pneumonia Model

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
David R. Andes
Keyword(s):  
Streptococcus Pneumoniae ◽  
Dose Range ◽  
Pharmacokinetic Parameters ◽  
Infection Model ◽  
Human Pharmacokinetics ◽  
Epithelial Lining Fluid ◽  
Content Type ◽  
Further Development

ABSTRACT Omadacycline is a novel aminomethylcycline antibiotic in clinical development for community-acquired bacterial pneumonia (CABP). We used a neutropenic murine pneumonia infection model to characterize the in vivo pharmacodynamic activity of omadacycline against Streptococcus pneumoniae. Four strains with various phenotypic resistances to other antimicrobials, including tetracyclines, were utilized. Drug concentration measurements were performed in the plasma and epithelial lining fluid (ELF) after administration of 0.5, 2, 8, and 32 mg/kg. Pharmacokinetic parameters were calculated using a noncompartmental model and were linear over the dose range. Penetration into ELF ranged from 72 to 102%. Omadacycline demonstrated net cidal activity in relation to the initial burden against all four strains. The pharmacokinetic/pharmacodynamic index AUC/MIC correlated well with efficacy (R 2 = 0.74). The plasma 24-h static dose AUC/MIC values were 16 to 20 (24-h ELF AUC/MIC of 14 to 18). A 1-log10 kill was achieved at 24-h plasma AUC/MIC values of 6.1 to 180 (24-h ELF AUC/MIC values 6.0 to 200). A 2-log10 kill was achieved at 24-h plasma AUC/MIC values of 19 to 56 (24-h ELF AUC/MIC of 17 to 47). The targets identified in this study in combination with in vitro potency and favorable human pharmacokinetics make omadacycline an attractive candidate for further development and study in patients with CABP.

scholarly journals Streptococcus pneumoniae DNA Initiates Type I Interferon Signaling in the Respiratory Tract

mBio ◽  
2011 ◽  
Vol 2 (3) ◽  
Author(s):  
Dane Parker ◽  
Francis J. Martin ◽  
Grace Soong ◽  
Bryan S. Harfenist ◽  
Jorge L. Aguilar ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Type I Interferon ◽  
Bacterial Pathogen ◽  
Central Component ◽  
Type I ◽  
Respiratory Pathogens ◽  
Airway Epithelial ◽  
Type I Ifn ◽  
Mucosal Epithelium ◽  
Content Type

ABSTRACTThe mucosal epithelium is the initial target for respiratory pathogens of all types. While type I interferon (IFN) signaling is traditionally associated with antiviral immunity, we demonstrate that the extracellular bacterial pathogenStreptococcus pneumoniaeactivates the type I IFN cascade in airway epithelial and dendritic cells. This response is dependent upon the pore-forming toxin pneumolysin. Pneumococcal DNA activates IFN-β expression through a DAI/STING/TBK1/IRF3 cascade.Tlr4−/−,Myd88−/−,Trif−/−, andNod2−/−mutant mice had no impairment of type I IFN signaling. Induction of type I IFN signaling contributes to the eradication of pneumococcal carriage, as IFN-α/β receptor null mice had significantly increased nasal colonization withS. pneumoniaecompared with that of wild-type mice. These studies suggest that the type I IFN cascade is a central component of the mucosal response to airway bacterial pathogens and is responsive to bacterial pathogen-associated molecular patterns that are capable of accessing intracellular receptors.IMPORTANCEThe bacteriumStreptococcus pneumoniaeis a leading cause of bacterial pneumonia, leading to upwards of one million deaths a year worldwide and significant economic burden. Although it is known that antibody is critical for efficient phagocytosis, it is not known how this pathogen is sensed by the mucosal epithelium. We demonstrate that this extracellular pathogen activates mucosal signaling typically activated by viral pathogens via the pneumolysin pore to activate intracellular receptors and the type I interferon (IFN) cascade. Mice lacking the receptor to type I IFNs have a reduced ability to clearS. pneumoniae, suggesting that the type I IFN cascade is central to the mucosal clearance of this important pathogen.

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