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Increased lethality and defective pulmonary clearance of Streptococcus pneumoniae in microsomal prostaglandin E synthase-1-knockout mice.
Dolan JM, Weinberg JB, O'Brien E, Abashian A, Procario MC, Aronoff DM, Crofford LJ, Peters-Golden M, Ward L, Mancuso P
(2016) Am J Physiol Lung Cell Mol Physiol 310: L1111-20
MeSH Terms: Animals, Cyclooxygenase 1, Cytokines, Dinoprostone, Female, Immunity, Innate, Lung, Macrophages, Alveolar, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Microsomes, Nitric Oxide, Pneumonia, Pneumococcal, Streptococcus pneumoniae
Show Abstract · Added June 2, 2017
The production of prostaglandin E2 (PGE2) increases dramatically during pneumococcal pneumonia, and this lipid mediator impairs alveolar macrophage (AM)-mediated innate immune responses. Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme involved in the synthesis of PGE2, and its expression is enhanced during bacterial infections. Genetic deletion of mPGES-1 in mice results in diminished PGE2 production and elevated levels of other prostaglandins after infection. Since PGE2 plays an important immunoregulatory role during bacterial pneumonia we assessed the impact of mPGES-1 deletion in the host defense against pneumococcal pneumonia in vivo and in AMs in vitro. Wild-type (WT) and mPGES-1 knockout (KO) mice were challenged with Streptococcus pneumoniae via the intratracheal route. Compared with WT animals, we observed reduced survival and increased lung and spleen bacterial burdens in mPGES-1 KO mice 24 and 48 h after S. pneumoniae infection. While we found modest differences between WT and mPGES-1 KO mice in pulmonary cytokines, AMs from mPGES-1 KO mice exhibited defective killing of ingested bacteria in vitro that was associated with diminished inducible nitric oxide synthase expression and reduced nitric oxide (NO) synthesis. Treatment of AMs from mPGES-1 KO mice with an NO donor restored bacterial killing in vitro. These results suggest that mPGES-1 plays a critical role in bacterial pneumonia and that genetic ablation of this enzyme results in diminished pulmonary host defense in vivo and in vitro. These results suggest that specific inhibition of PGE2 synthesis by targeting mPGES-1 may weaken host defense against bacterial infections.
Copyright © 2016 the American Physiological Society.
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15 MeSH Terms
Myeloid-related protein-8/14 facilitates bacterial growth during pneumococcal pneumonia.
Achouiti A, Vogl T, Endeman H, Mortensen BL, Laterre PF, Wittebole X, van Zoelen MA, Zhang Y, Hoogerwerf JJ, Florquin S, Schultz MJ, Grutters JC, Biesma DH, Roth J, Skaar EP, van 't Veer C, de Vos AF, van der Poll T
(2014) Thorax 69: 1034-42
MeSH Terms: Animals, Bronchoalveolar Lavage Fluid, Calgranulin B, Disease Models, Animal, Female, Humans, Lung, Male, Mice, Mice, Inbred C57BL, Pneumonia, Pneumococcal, Streptococcus pneumoniae
Show Abstract · Added January 24, 2015
BACKGROUND - Streptococcus pneumoniae is the most commonly identified pathogen in community-acquired pneumonia (CAP). Myeloid-related protein (MRP) 8/14 is a major component of neutrophils that is released upon infection or injury. MRP8/14 is essential for protective immunity during infection by a variety of micro-organisms through its capacity to chelate manganese and zinc. Here, we aimed to determine the role of MRP8/14 in pneumococcal pneumonia.
METHODS - MRP8/14 was determined in bronchoalveolar lavage fluid (BALF) and serum of CAP patients, in lung tissue of patients who had succumbed to pneumococcal pneumonia, and in BALF of healthy subjects challenged with lipoteichoic acid (a component of the gram-positive bacterial cell wall) via the airways. Pneumonia was induced in MRP14 deficient and normal wildtype mice. The effect of MRP8/14 on S. pneumoniae growth was studied in vitro.
RESULTS - CAP patients displayed high MRP8/14 levels in BALF, lung tissue and serum. Healthy subjects challenged with lipoteichoic acid demonstrated elevated MRP8/14 in BALF. Likewise, mice with pneumococcal pneumonia had high MRP8/14 levels in lungs and the circulation. MRP14 deficiency, however, was associated with reduced bacterial growth and lethality, in the absence of notable effects on the inflammatory response. High zinc levels strongly inhibited growth of S. pneumoniae in vitro, which was partially reversed by MRP8/14.
CONCLUSIONS - In sharp contrast to its previously reported host-protective role in several infections, the present results reveal that in a model of CAP, MRP8/14 is misused by S. pneumoniae, facilitating bacterial growth by attenuating zinc toxicity toward the pathogen.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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12 MeSH Terms
Unveiling the burden of influenza-associated pneumococcal pneumonia.
Grijalva CG, Griffin MR
(2012) J Infect Dis 205: 355-7
MeSH Terms: Animals, Bronchopneumonia, Carrier State, Female, Ferrets, Host-Pathogen Interactions, Humans, Influenza A virus, Male, Metapneumovirus, Orthomyxoviridae, Orthomyxoviridae Infections, Paramyxoviridae Infections, Platelet Membrane Glycoproteins, Pneumococcal Infections, Pneumococcal Vaccines, Pneumonia, Pneumococcal, Pneumonia, Viral, Population Surveillance, Receptors, Cell Surface, Receptors, G-Protein-Coupled, Streptococcus pneumoniae
Added July 27, 2018
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MeSH Terms
Toll-like receptor 2 mediates fatal immunopathology in mice during treatment of secondary pneumococcal pneumonia following influenza.
Karlström A, Heston SM, Boyd KL, Tuomanen EI, McCullers JA
(2011) J Infect Dis 204: 1358-66
MeSH Terms: Animals, Anti-Bacterial Agents, Female, Immunologic Factors, Lung, Macrolides, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neutrophils, Orthomyxoviridae Infections, Pneumonia, Pneumococcal, Streptococcus pneumoniae, Toll-Like Receptor 2, Treatment Outcome, beta-Lactams
Show Abstract · Added March 20, 2014
Host inflammatory responses contribute to the significant immunopathology that occurs during treatment of secondary bacterial pneumonia following influenza. We undertook the present study to determine the mechanisms underlying disparate outcomes in a mouse model with β-lactam and macrolide antibiotics. Lysis of superinfecting bacteria by ampicillin caused an extensive influx of neutrophils into the lungs resulting in a consolidative pneumonia, necrotic lung damage, and significant mortality. This was mediated through Toll-like receptor (TLR) 2 and was independent of TLR4 and the Streptococcus pneumoniae cytotoxin pneumolysin. Treatment with azithromycin prevented neutrophil accumulation and rescued mice from subsequent mortality. This effect was independent of the antibacterial activity of this macrolide since dual therapy with ampicillin and azithromycin against an azithromycin-resistant strain also was able to cure secondary pneumonia. These data suggest that strategies for eliminating bacteria without lysis coupled with immunomodulation of inflammation should be pursued clinically.
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17 MeSH Terms
Emergence of parapneumonic empyema in the USA.
Grijalva CG, Zhu Y, Nuorti JP, Griffin MR
(2011) Thorax 66: 663-8
MeSH Terms: Adolescent, Adult, Aged, Empyema, Pleural, Female, Hospitalization, Humans, Incidence, Length of Stay, Male, Middle Aged, Pneumonia, Bacterial, Pneumonia, Pneumococcal, Pneumonia, Staphylococcal, Streptococcal Infections, United States, Young Adult
Show Abstract · Added December 10, 2013
BACKGROUND - Although recent reports suggest that the incidence of parapneumonic empyema has increased in several regions of the USA, national trends in disease burden are unknown. National trends in the incidence of parapneumonic empyema hospitalisations and changes in empyema by associated pathogens were examined.
METHODS - National hospitalisation data (1996-2008) were analysed and rates estimated using census estimates as denominators. Incidence rate ratios (IRR) compared 2008 with 1996 rates. Discharge diagnosis codes were used to characterise pathogens associated with empyema hospitalisations.
RESULTS - Overall, national parapneumonic empyema-related hospitalisation rates increased from 3.04 per 100,000 in 1996 to 5.98 per 100,000 in 2008, a 2.0-fold increase (95% CI 1.8 to 2.1). The increases were observed among children (IRR 1.9 (95% CI 1.4 to 2.7)) and adults aged 18-39, 40-64 and ≥65 years (IRR 1.8 (95% CI 1.5 to 2.1), 2.0 (95% CI 1.6 to 3.1) and 1.7 (95% CI 1.5 to 2.0), respectively). Overall, pneumococcal empyema rates remained relatively stable in all age groups whereas streptococcal- (non-pneumococcal) and staphylococcal-related empyema rates increased 1.9-fold and 3.3-fold, respectively, with consistent increases across age groups. The overall in-hospital case fatality ratio for parapneumonic empyema-related hospitalisations was 8.0% (95% CI 6.4% to 9.5%) in 1996 and 7.2% (95% CI 6.3% to 8.1%) in 2008 (p=0.395). Of the empyemas where study pathogens were listed (37.6%), staphylococcal-related empyema had the largest absolute increases across age groups and was associated with longer hospital stay and higher in-hospital mortality than other empyemas.
CONCLUSIONS - Although parapneumonic empyema-related hospitalisations remained relatively rare, they increased substantially during the study period. A number of pathogens, especially staphylococcus, contributed to this increase.
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17 MeSH Terms
Immunotherapy with a combination of intravenous immune globulin and p4 peptide rescues mice from postinfluenza pneumococcal pneumonia.
Weeks JN, Boyd KL, Rajam G, Ades EW, McCullers JA
(2011) Antimicrob Agents Chemother 55: 2276-81
MeSH Terms: Animals, Female, Immunoglobulins, Intravenous, Immunotherapy, Mice, Mice, Inbred BALB C, Pneumonia, Pneumococcal, Streptococcus pneumoniae
Show Abstract · Added March 20, 2014
Alternate therapies are needed for treatment of secondary bacterial pneumonia following influenza. The immunomodulatory peptide P4 has shown promise in mouse models of primary pneumococcal infection. Mice infected with influenza virus and then challenged with Streptococcus pneumoniae were treated with a combination of P4 peptide and intravenous immune globulin. Survival was improved from 20% to 80% in treated mice relative to controls. Clinical cure correlated with increased clearance of bacteria and decreased lung consolidation. Greater trafficking of professional phagocytic cells to the site of pneumococcal infection coupled with enhanced opsonophagocytosis as manifest by decreased surface display of Fcγ receptors (FcγR) on neutrophils and macrophages were associated with P4 peptide treatment. This suggests that the mechanism of action for improved clearance of bacteria engendered by P4 is through improved uptake by phagocytes mediated by IgG Fc-Fcγ receptor interactions following antibody-mediated opsonophagocytosis of bacteria. Antibody-based therapies, when coupled with immune modulators, such as P4 peptide, may be an effective tool together with antibiotics in our armamentarium against severe pneumonia.
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8 MeSH Terms
Intrapulmonary administration of leukotriene B4 enhances pulmonary host defense against pneumococcal pneumonia.
Mancuso P, Lewis C, Serezani CH, Goel D, Peters-Golden M
(2010) Infect Immun 78: 2264-71
MeSH Terms: Administration, Inhalation, Aerosols, Animals, Arachidonate 5-Lipoxygenase, Biological Products, Colony Count, Microbial, Cytokines, Immunologic Factors, Injections, Intraperitoneal, Injections, Intravenous, Leukocyte Count, Leukotriene B4, Lung, Mice, Mice, Knockout, Pneumonia, Pneumococcal, Streptococcus pneumoniae
Show Abstract · Added May 4, 2017
Leukotriene B(4) (LTB(4)) is a potent lipid mediator of inflammation formed by the 5-lipoxygenase (5-LO)-catalyzed oxidation of arachidonic acid. We have previously shown that (i) LTB(4) is generated during infection, (ii) its biosynthesis is essential for optimal antimicrobial host defense, (iii) LT deficiency is associated with clinical states of immunocompromise, and (iv) exogenous LTB(4) augments antimicrobial functions in phagocytes. Here, we sought to determine whether the administration of LTB(4) has therapeutic potential in a mouse model of pneumonia. Wild-type and 5-LO knockout mice were challenged with Streptococcus pneumoniae via the intranasal route, and bacterial burdens, leukocyte counts, and cytokine levels were determined. LTB(4) was administered via the intraperitoneal, intravenous, and intranasal routes prior to pneumococcal infection and by aerosol 24 h following infection. Leukocytes recovered from mice given S. pneumoniae and treated with aerosolized LTB(4) were evaluated for expression levels of the p47phox subunit of NADPH oxidase. Intrapulmonary but not systemic pretreatment with LTB(4) significantly reduced the lung S. pneumoniae burden in wild-type mice. Aerosolized LTB(4) was effective at improving lung bacterial clearance when administered postinoculation in animals with established infection and exhibited greater potency in 5-LO knockout animals, which also exhibited greater baseline susceptibility. Augmented bacterial clearance in response to LTB(4) was associated with enhanced monocyte recruitment and leukocyte expression of p47phox. The results of the current study in an animal model serve as a proof of concept for the potential utility of treatment with aerosolized LTB(4) as an immunostimulatory strategy in patients with bacterial pneumonia.
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17 MeSH Terms
E-prostanoid 3 receptor deletion improves pulmonary host defense and protects mice from death in severe Streptococcus pneumoniae infection.
Aronoff DM, Lewis C, Serezani CH, Eaton KA, Goel D, Phipps JC, Peters-Golden M, Mancuso P
(2009) J Immunol 183: 2642-9
MeSH Terms: Alprostadil, Animals, Dinoprostone, Female, Immunity, Innate, Inflammation Mediators, Lipopolysaccharides, Lung, Mice, Mice, Inbred C57BL, Mice, Knockout, Pneumonia, Pneumococcal, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP3 Subtype, Severity of Illness Index, Signal Transduction
Show Abstract · Added May 4, 2017
Prostaglandins (PGs) are potent lipid mediators that are produced during infections and whose synthesis and signaling networks present potential pharmacologic targets for immunomodulation. PGE(2) acts through the ligation of four distinct G protein-coupled receptors, E-prostanoid (EP) 1-4. Previous in vitro and in vivo studies demonstrated that the activation of the G(alphas)-coupled EP2 and EP4 receptors suppresses inflammatory responses to microbial pathogens through cAMP-dependent signaling cascades. Although it is speculated that PGE(2) signaling via the G(alphai)-coupled EP3 receptor might counteract EP2/EP4 immunosuppression in the context of bacterial infection (or severe inflammation), this has not previously been tested in vivo. To address this, we infected wild-type (EP3(+/+)) and EP3(-/-) mice with the important respiratory pathogen Streptococcus pneumoniae or injected mice i.p. with LPS. Unexpectedly, we observed that EP3(-/-) mice were protected from mortality after infection or LPS. The enhanced survival observed in the infected EP3(-/-) mice correlated with enhanced pulmonary clearance of bacteria; reduced accumulation of lung neutrophils; lower numbers of circulating blood leukocytes; and an impaired febrile response to infection. In vitro studies revealed improved alveolar macrophage phagocytic and bactericidal capacities in EP3(-/-) cells that were associated with an increased capacity to generate NO in response to immune stimulation. Our studies underscore the complex nature of PGE(2) immunomodulation in the context of host-microbial interactions in the lung. Pharmacological targeting of the PGE(2)-EP3 axis represents a novel area warranting greater investigative interest in the prevention and/or treatment of infectious diseases.
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16 MeSH Terms
Recognising pneumonia burden through prevention.
Grijalva CG
(2009) Vaccine 27 Suppl 3: C6-8
MeSH Terms: Adolescent, Adult, Age Distribution, Child, Child, Preschool, Heptavalent Pneumococcal Conjugate Vaccine, Humans, Longitudinal Studies, Middle Aged, Pneumococcal Vaccines, Pneumonia, Pneumococcal, United States, Vaccines, Conjugate, Young Adult
Show Abstract · Added July 27, 2018
Streptococcus pneumoniae is an important cause of otitis media, sinusitis, pneumonia, and invasive pneumococcal diseases (IPDs) such as meningitis, bacteremia, and bacteremic pneumonia. Globally, pneumonia is the leading cause of death in children aged <5 years. After the implementation of routine immunisation with a seven-valent pneumococcal conjugate vaccine (PCV7) in the United States in 2000, a substantial decline in pneumonia-related hospitalisations among children aged <2 years was observed. In this age group, there was a 39% and 65% reduction in rates of all-cause and pneumococcal pneumonia hospitalisations, respectively, indicating a direct effect of routine immunisation with PCV7.
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MeSH Terms
Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling.
Medeiros AI, Serezani CH, Lee SP, Peters-Golden M
(2009) J Exp Med 206: 61-8
MeSH Terms: Adenylyl Cyclase Inhibitors, Animals, Apoptosis, Culture Media, Conditioned, Cyclic AMP, Cyclooxygenase Inhibitors, Dinoprostone, Humans, Interleukin-10, Jurkat Cells, Lung, Macrophages, Alveolar, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils, Phagocytosis, Pneumonia, Pneumococcal, Prostaglandin Antagonists, Rats, Rats, Wistar, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP2 Subtype, Signal Transduction, Streptococcus pneumoniae, T-Lymphocytes
Show Abstract · Added May 4, 2017
The ingestion of apoptotic cells (ACs; termed "efferocytosis") by phagocytes has been shown to trigger the release of molecules such as transforming growth factor beta, interleukin-10 (IL-10), nitric oxide, and prostaglandin E(2) (PGE(2)). Although the antiinflammatory actions of these mediators may contribute to the restoration of homeostasis after tissue injury, their potential impact on antibacterial defense is unknown. The lung is highly susceptible to diverse forms of injury, and secondary bacterial infections after injury are of enormous clinical importance. We show that ACs suppress in vitro phagocytosis and bacterial killing by alveolar macrophages and that this is mediated by a cyclooxygenase-PGE(2)-E prostanoid receptor 2 (EP2)-adenylyl cyclase-cyclic AMP pathway. Moreover, intrapulmonary administration of ACs demonstrated that PGE(2) generated during efferocytosis and acting via EP2 accounts for subsequent impairment of lung recruitment of polymorphonuclear leukocytes and clearance of Streptococcus pneumoniae, as well as enhanced generation of IL-10 in vivo. These results suggest that in addition to their beneficial homeostatic influence, antiinflammatory programs activated by efferocytosis in the lung have the undesirable potential to dampen innate antimicrobial responses. They also identify an opportunity to reduce the incidence and severity of pneumonia in the setting of lung injury by pharmacologically targeting synthesis of PGE(2) or ligation of EP2.
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26 MeSH Terms