Enhanced vulnerability for Streptococcus pneumoniae sepsis during asplenia is determined by the bacterial capsule

Lammers, A.J.J.; Porto, Alexander P. N. A. de; Florquin, Sandrine; Boer, Onno J. de; Bootsma, Hester J.; Hermans, Peter W. M.; Poll, Tom van der

doi:10.1016/j.imbio.2011.02.004

Cited by 25 publications

(35 citation statements)

References 31 publications

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“…As expected (11)(12)(13), Spneu induced microscopic features typical for pneumonia, characterized by neutrophil influx, interstitial damage, endothelialitis, bronchitis, edema and pleuritis. Consistent with previous reports (11)(12)(13), bacterial loads decreased between 6 and 48 h after infection.…”

Section: Differential Host Gene Expression During Pneumococcal Pneumoniasupporting

confidence: 80%

“…A suspension of 2 × 10 7 colony-forming units (CFUs) in 50 μL isotonic saline was used as the inoculum. Mice were lightly anaesthetized by inhalation of 2.0%-2.5% isoflurane (Upjohn, Ede, the Netherlands) mixed with O 2 (1-2 L/min) and intranasally challenged as previously described (11,12). Mice were humanely euthanized at 6 or 48 h postinfection (n = 4 at each time point).…”

Section: Induction Of Pneumonia and Bacterial Burden Assessmentmentioning

confidence: 99%

“…Mice were humanely euthanized at 6 or 48 h postinfection (n = 4 at each time point). Lung tissue was harvested and processed for the determination of bacterial outgrowth as described (11,12). CFUs in lung homogenates were determined from serial dilutions plated on blood agar plates incubated at 37°C for 16 h before colonies were counted.…”

Section: Induction Of Pneumonia and Bacterial Burden Assessmentmentioning

confidence: 99%

“…Sections (5 μm) were stained with hematoxylin and eosin (HE). Granulocyte staining was performed by anti-Ly6G hybdridization and quantified by means of ImageJ software (Bethesda, MD, USA; http://rsb.info.nih.gov/ij/) as previously described (12,13).…”

Section: Lung Histopathologymentioning

confidence: 99%

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Modular Transcriptional Networks of the Host Pulmonary Response during Early and Late Pneumococcal Pneumonia

Scicluna

Lieshout

Blok

et al. 2015

Mol Med

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Streptococcus pneumoniae (Spneu) remains the most lethal bacterial pathogen and the dominant agent of communityacquired pneumonia. Treatment has perennially focused on the use of antibiotics, albeit scrutinized due to the occurrence of antibiotic-resistant Spneu strains. Immunomodulatory strategies have emerged as potential treatment options. Although promising, immunomodulation can lead to improper tissue functions either at steady state or upon infectious challenge. This argues for the availability of tools to enable a detailed assessment of whole pulmonary functions during the course of infection, not only those functions biased to the defense response. Thus, through the use of an unbiased tissue microarray and bioinformatics approach, we aimed to construct a comprehensive map of whole-lung transcriptional activity and cellular pathways during the course of pneumococcal pneumonia. We performed genome-wide transcriptional analysis of whole lungs before and 6 and 48 h after Spneu infection in mice. The 4,000 most variable transcripts across all samples were used to assemble a gene coexpression network comprising 13 intercorrelating modules (clusters of genes). Fifty-four percent of this whole-lung transcriptional network was altered 6 and 48 h after Spneu infection. Canonical signaling pathway analysis uncovered known pathways imparting protection, including IL17A/IL17F signaling and previously undetected mechanisms that included lipid metabolism. Through in silico prediction of cell types, pathways were observed to enrich for distinct cell types such as a novel stromal cell lipid metabolism pathway. These cellular mechanisms were furthermore anchored at functional hub genes of cellular fate, differentiation, growth and transcription. Collectively, we provide a benchmark unsupervised map of whole-lung transcriptional relationships and cellular activity during early and late pneumococcal pneumonia.

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Section: Differential Host Gene Expression During Pneumococcal Pneumoniasupporting

confidence: 80%

Section: Induction Of Pneumonia and Bacterial Burden Assessmentmentioning

confidence: 99%

Section: Induction Of Pneumonia and Bacterial Burden Assessmentmentioning

confidence: 99%

Section: Lung Histopathologymentioning

confidence: 99%

See 2 more Smart Citations

Modular Transcriptional Networks of the Host Pulmonary Response during Early and Late Pneumococcal Pneumonia

Scicluna

Lieshout

Blok

et al. 2015

Mol Med

Self Cite

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“…32 Functional asplenia is operative both in murine and human SCA, but hydroxyurea only improves spleen function when HbF levels are increased. 15,33 The lack of HbF in the SCA murine model exposes the HbFindependent effects of hydroxyurea and thus focuses on the benefit of hydroxyurea independently of the spleen.…”

Section: Discussionmentioning

confidence: 99%

Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

Lebensburger¹,

Howard²,

Hu³

et al. 2012

Blood

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Sickle cell anemia is characterized by chronic hemolysis coupled with extensive vascular inflammation. This inflammatory state also mechanistically promotes a high risk of lethal, invasive pneumococcal infection. Current treatments to reduce vaso-occlusive complications include chronic hydroxyurea therapy to induce fetal hemoglobin. Because hydroxyurea also reduces leukocytosis, an understanding of the impact of this treatment on pneumococcal pathogenesis is needed. Using a sickle cell mouse model of pneumococcal pneumonia and sepsis, administration of hydroxyurea was found to significantly improve survival. Hydroxyurea treatment decreased neutrophil extravasation into the infected lung coincident with significantly reduced levels of E-selectin in serum and on pulmonary epithelia. The protective effect of hydroxyurea was abrogated in mice deficient in E-selectin. The decrease in Eselectin levels was also evident in human sickle cell patients receiving hydroxyurea therapy. These data indicate that in addition to induction of fetal hemoglobin, hydroxyurea attenuates leukocyteendothelial interactions in sickle cell anemia, resulting in protection against lethal pneumococcal sepsis. IntroductionSickle cell anemia (SCA) is characterized by chronic hemolytic anemia and vascular inflammation. Hydroxyurea therapy decreases vasoocclusive complications of SCA and reduces mortality, 1,2 but the mechanism of this benefit has been debated. Elevated white blood cell counts have been found to correlate with greater mortality in sickle cell disease (SCD), 3 and early studies suggested hydroxyurea reduced leukocytosis. 4,5 Subsequent studies found no statistical association between reduction of leukocytosis and mortality in SCA patients receiving hydroxyurea, implicating increased levels of hemoglobin F (HbF) as the main predictor of mortality. 6 A recent placebo-controlled clinical trial of hydroxyurea in pediatric SCA patients confirmed a highly significant decrease in total white blood cell and absolute neutrophil counts after hydroxyurea treatment as well as increases in hemoglobin and HbF levels. 7 A significant decrease in acute chest syndrome, which is oftentimes initiated by lung infection, also was observed in this study. 7 Bacteremia was recorded 6 times in the placebo group but only 3 times in the hydroxyurea-treated patients, 7 a trend that was not significant because of the low incidence. Although induction of HbF is generally accepted to be a major benefit of hydroxyurea therapy in SCA, the relative contribution of other factors, including decreased white blood cell counts, to positive outcomes remains a possibility that has yet to be explored.Modulation of leukocytosis by hydroxyurea raises the question of infection risk in SCA. Children with SCA have a 400-fold greater risk of fulminant, lethal pneumococcal sepsis than their healthy peers or patients with other hemolytic anemias, 8-10 a finding recapitulated in the sickle cell mouse model. 11 Despite administration of penicillin prophylaxis, pneumococcal polysac...

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Hyposplenism: Comparison of different methods for determining splenic function

et al. 2012

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Asplenic patients are at risk for pneumococcal sepsis. Patients with hyposplenic function, such as associated with sickle cell disease (SCD), are also at risk. However, tests to assess splenic function are either unavailable or lacking standardization. The aim of this study was to compare different methods for determining splenic function. Eighteen patients with SCD (i.e., 10 heterozygous (SC) and 8 homozygous (SS) SCD patients), and eight splenectomized patients were compared to 10 controls. All subjects underwent spleen scintigraphy, after which functional splenic volumes (FSV) were calculated. FSV was compared to immunological function and B cell-subsets, as well as phagocytic function represented by the presence of Howell Jolly bodies (HJB) and percentages of pitted red cells (PIT). Heterozygous SCD (SC) patients had increased splenic volumes, but diminished FSV, homozygous SCD (SS) patients were asplenic. Splenectomized and SS patients had a strongly reduced phagocytic and immunological function. SC patients had reduced anti-polysaccharide responses without an increase in PIT. FSV correlated significantly with phagocytic and immunological function. HJB were indicative of splenic dysfunction, HJB absence was not indicative of normal functioning splenic tissue. Although visualizing HJB is methodologically advantageous to PIT, both are valid biomarkers of splenic dysfunction. The amount of non-switched memory B cells is strongly correlated to FSV. Am. J. Hematol. 87:484-489, 2012. V

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Enhanced vulnerability for Streptococcus pneumoniae sepsis during asplenia is determined by the bacterial capsule

Cited by 25 publications

References 31 publications

Modular Transcriptional Networks of the Host Pulmonary Response during Early and Late Pneumococcal Pneumonia

Modular Transcriptional Networks of the Host Pulmonary Response during Early and Late Pneumococcal Pneumonia

Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

Hyposplenism: Comparison of different methods for determining splenic function

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