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Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus pneumoniae infection.
Salina AC, Souza TP, Serezani CH, Medeiros AI
(2017) Innate Immun 23: 219-227
MeSH Terms: Animals, Apoptosis, Bacteriolysis, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Dinoprostone, Female, Homeostasis, Humans, Hydrogen Peroxide, Jurkat Cells, Macrophages, Alveolar, Phagocytosis, Pneumococcal Infections, Rats, Rats, Wistar, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, Streptococcus pneumoniae
Show Abstract · Added May 4, 2017
Alveolar macrophages (AMs) are multitasking cells that maintain lung homeostasis by clearing apoptotic cells (efferocytosis) and performing antimicrobial effector functions. Different PRRs have been described to be involved in the binding and capture of non-opsonized Streptococcus pneumoniae, such as TLR-2, mannose receptor (MR) and scavenger receptors (SRs). However, the mechanism by which the ingestion of apoptotic cells negatively influences the clearance of non-opsonized S. pneumoniae remains to be determined. In this study, we evaluated whether the prostaglandin E2 (PGE) produced during efferocytosis by AMs inhibits the ingestion and killing of non-opsonized S. pneumoniae. Resident AMs were pre-treated with an E prostanoid (EP) receptor antagonist, inhibitors of cyclooxygenase and protein kinase A (PKA), incubated with apoptotic Jurkat T cells, and then challenged with S. pneumoniae. Efferocytosis slightly decreased the phagocytosis of S. pneumoniae but greatly inhibited bacterial killing by AMs in a manner dependent on PGE production, activation of the EP2-EP4/cAMP/PKA pathway and inhibition of HO production. Our data suggest that the PGE produced by AMs during efferocytosis inhibits HO production and impairs the efficient clearance non-opsonized S. pneumoniae by EP2-EP4/cAMP/PKA pathway.
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20 MeSH Terms
Nasopharyngeal Pneumococcal Density and Evolution of Acute Respiratory Illnesses in Young Children, Peru, 2009-2011.
Fan RR, Howard LM, Griffin MR, Edwards KM, Zhu Y, Williams JV, Vidal JE, Klugman KP, Gil AI, Lanata CF, Grijalva CG
(2016) Emerg Infect Dis 22: 1996-1999
MeSH Terms: Acute Disease, Bacterial Load, Child, Preschool, Cross-Sectional Studies, Female, Humans, Infant, Infant, Newborn, Male, Nasopharynx, Peru, Pneumococcal Infections, Pneumococcal Vaccines, Population Surveillance, Respiratory Tract Infections, Risk Factors, Streptococcus pneumoniae
Show Abstract · Added July 27, 2018
We examined nasopharyngeal pneumococcal colonization density patterns surrounding acute respiratory illnesses (ARI) in young children in Peru. Pneumococcal densities were dynamic, gradually increasing leading up to an ARI, peaking during the ARI, and decreasing after the ARI. Rhinovirus co-infection was associated with higher pneumococcal densities.
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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
Bacterial Density, Serotype Distribution and Antibiotic Resistance of Pneumococcal Strains from the Nasopharynx of Peruvian Children Before and After Pneumococcal Conjugate Vaccine 7.
Hanke CR, Grijalva CG, Chochua S, Pletz MW, Hornberg C, Edwards KM, Griffin MR, Verastegui H, Gil AI, Lanata CF, Klugman KP, Vidal JE
(2016) Pediatr Infect Dis J 35: 432-9
MeSH Terms: Anti-Bacterial Agents, Bacterial Load, Child, Preschool, Cross-Sectional Studies, Drug Resistance, Bacterial, Female, Heptavalent Pneumococcal Conjugate Vaccine, Humans, Infant, Male, Microbial Sensitivity Tests, Nasopharynx, Peru, Pneumococcal Infections, Prevalence, Serogroup, Streptococcus pneumoniae
Show Abstract · Added July 27, 2018
BACKGROUND - Pneumococcal conjugate vaccines (PCV) have decreased nasopharyngeal carriage of vaccine types but little data exist from rural areas. We investigated bacterial density, serotype distribution and antibiotic resistance of pneumococcal strains within the nasopharynx of young children in the Peruvian Andes, 2 years after PCV7 was introduced.
METHODS - Pneumococcal strains were isolated from a subset of 125 children from our Peruvian cohort, who entered the study in 2009 and had pneumococcus detected in the nasopharynx in both 2009 and during follow-up in 2011. Strains were Quellung serotyped and tested for susceptibility to antibiotics. Bacterial density was determined by quantitative polymerase chain reaction.
RESULTS - The prevalence of PCV7 strains decreased from 48% in 2009 to 28.8% in 2011, whereas non-PCV7 types increased from 52% to 71.2% (P = 0.002). There was a 3.5-fold increase in carriage of serotype 6C in 2011 (P = 0.026). Vaccination with PCV7 did not affect pneumococcal density in children colonized by a PCV7 type but did increase density in those colonized with a non-PCV7 type. Antibiotic resistance did not change after vaccine introduction; strains were nonsusceptible to tetracycline (97.2%), trimethoprim-sulfamethoxazole (56.4%), penicillin (34%), erythromycin (22.4%), chloramphenicol (18.8%) and clindamycin (12.4%).
CONCLUSIONS - Serotype replacement was observed post-PCV7 vaccination with a concomitant, not previously recognized, increased nasopharyngeal density.
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Corynebacterium accolens Releases Antipneumococcal Free Fatty Acids from Human Nostril and Skin Surface Triacylglycerols.
Bomar L, Brugger SD, Yost BH, Davies SS, Lemon KP
(2016) mBio 7: e01725-15
MeSH Terms: Anti-Bacterial Agents, Antibiosis, Carrier State, Child, Child, Preschool, Corynebacterium, Fatty Acids, Nonesterified, Humans, Hydrolysis, Infant, Microbiota, Nasal Cavity, Pneumococcal Infections, Skin, Streptococcus pneumoniae, Triglycerides, Triolein
Show Abstract · Added July 17, 2019
UNLABELLED - Bacterial interspecies interactions play clinically important roles in shaping microbial community composition. We observed that Corynebacterium spp. are overrepresented in children free of Streptococcus pneumoniae (pneumococcus), a common pediatric nasal colonizer and an important infectious agent. Corynebacterium accolens, a benign lipid-requiring species, inhibits pneumococcal growth during in vitro cocultivation on medium supplemented with human skin surface triacylglycerols (TAGs) that are likely present in the nostrils. This inhibition depends on LipS1, a TAG lipase necessary for C. accolens growth on TAGs such as triolein. We determined that C. accolens hydrolysis of triolein releases oleic acid, which inhibits pneumococcus, as do other free fatty acids (FFAs) that might be released by LipS1 from human skin surface TAGs. Our results support a model in which C. accolens hydrolyzes skin surface TAGS in vivo releasing antipneumococcal FFAs. These data indicate that C. accolens may play a beneficial role in sculpting the human microbiome.
IMPORTANCE - Little is known about how harmless Corynebacterium species that colonize the human nose and skin might impact pathogen colonization and proliferation at these sites. We show that Corynebacterium accolens, a common benign nasal bacterium, modifies its local habitat in vitro as it inhibits growth of Streptococcus pneumoniae by releasing antibacterial free fatty acids from host skin surface triacylglycerols. We further identify the primary C. accolens lipase required for this activity. We postulate a model in which higher numbers of C. accolens cells deter/limit S. pneumoniae nostril colonization, which might partly explain why children without S. pneumoniae colonization have higher levels of nasal Corynebacterium. This work narrows the gap between descriptive studies and the needed in-depth understanding of the molecular mechanisms of microbe-microbe interactions that help shape the human microbiome. It also lays the foundation for future in vivo studies to determine whether habitat modification by C. accolens could be promoted to control pathogen colonization.
Copyright © 2016 Bomar et al.
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Restraining the pneumococcus.
Griffin MR, Grijalva CG
(2015) Lancet Infect Dis 15: 491-2
MeSH Terms: Female, Humans, Male, Mass Vaccination, Pneumococcal Infections, Pneumococcal Vaccines, Streptococcus pneumoniae
Added July 27, 2018
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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
The role of influenza and parainfluenza infections in nasopharyngeal pneumococcal acquisition among young children.
Grijalva CG, Griffin MR, Edwards KM, Williams JV, Gil AI, Verastegui H, Hartinger SM, Vidal JE, Klugman KP, Lanata CF
(2014) Clin Infect Dis 58: 1369-76
MeSH Terms: Case-Control Studies, Child, Preschool, Cohort Studies, Female, Humans, Infant, Infant, Newborn, Influenza, Human, Male, Microbial Interactions, Nasopharynx, Orthomyxoviridae, Paramyxoviridae, Paramyxoviridae Infections, Peru, Prospective Studies, Respiratory Tract Infections, Risk Factors, Serotyping, Streptococcus pneumoniae
Show Abstract · Added May 28, 2014
BACKGROUND - Animal models suggest that influenza infection favors nasopharyngeal acquisition of pneumococci. We assessed this relationship with influenza and other respiratory viruses in young children.
METHODS - A case-control study was nested within a prospective cohort study of acute respiratory illness (ARI) in Andean children <3 years of age (RESPIRA-PERU study). Weekly household visits were made to identify ARI and obtain nasal swabs for viral detection using real-time reverse-transcription polymerase chain reaction. Monthly nasopharyngeal (NP) samples were obtained to assess pneumococcal colonization. We determined whether specific respiratory viral ARI episodes occurring within the interval between NP samples increased the risk of NP acquisition of new pneumococcal serotypes.
RESULTS - A total of 729 children contributed 2128 episodes of observation, including 681 pneumococcal acquisition episodes (new serotype, not detected in prior sample), 1029 nonacquisition episodes (no colonization or persistent colonization with the same serotype as the prior sample), and 418 indeterminate episodes. The risk of pneumococcal acquisition increased following influenza-ARI (adjusted odds ratio [AOR], 2.19; 95% confidence interval [CI], 1.02-4.69) and parainfluenza-ARI (AOR, 1.86; 95% CI, 1.15-3.01), when compared with episodes without ARI. Other viral infections (respiratory syncytial virus, human metapneumovirus, human rhinovirus, and adenovirus) were not associated with acquisition.
CONCLUSIONS - Influenza and parainfluenza ARIs appeared to facilitate pneumococcal acquisition among young children. As acquisition increases the risk of pneumococcal diseases, these observations are pivotal in our attempts to prevent pneumococcal disease.
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Distribution of pneumococcal serotypes in adult pneumococcal pneumonia cases: filling the evidence gap to inform vaccination policies.
Griffin MR, Grijalva CG
(2013) J Infect Dis 208: 1734-6
MeSH Terms: Community-Acquired Infections, Female, Humans, Male, Pneumococcal Infections, Pneumococcal Vaccines, Streptococcus pneumoniae
Added December 10, 2013
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Expression of Streptococcus pneumoniae Virulence-Related Genes in the Nasopharynx of Healthy Children.
Sakai F, Talekar SJ, Lanata CF, Grijalva CG, Klugman KP, Vidal JE, RESPIRA PERU Group, Investigators Group
(2013) PLoS One 8: e67147
MeSH Terms: Child, Genes, Bacterial, Humans, Nasopharynx, Polymerase Chain Reaction, Streptococcus pneumoniae, Virulence
Show Abstract · Added July 27, 2018
Colonization and persistence in the human nasopharynx are prerequisites for Streptococcus pneumoniae disease and carriage acquisition, which normally occurs during early childhood. Animal models and in vitro studies (i.e. cell adhesion and cell cytotoxicity assays) have revealed a number of colonization and virulence factors, as well as regulators, implicated in nasopharyngeal colonization and pathogenesis. Expression of genes encoding these factors has never been studied in the human nasopharynx. Therefore, this study analyzed expression of S. pneumoniae virulence-related genes in human nasopharyngeal samples. Our experiments first demonstrate that a density of ≥10(4) CFU/ml of S. pneumoniae cells in the nasopharynx provides enough DNA and RNA to amplify the lytA gene by conventional PCR and to detect the lytA message, respectively. A panel of 21 primers that amplified S. pneumoniae sequences was designed, and their specificity for S. pneumoniae sequences was analyzed in silico and validated against 20 related strains inhabitants of the human upper respiratory tract. These primers were utilized in molecular reactions to find out that all samples contained the genes ply, pavA, lytC, lytA, comD, codY, and mgrA, whereas nanA, nanB, pspA, and rrgB were present in ∼91-98% of the samples. Gene expression studies of these 11 targets revealed that lytC, lytA, pavA and comD were the most highly expressed pneumococcal genes in the nasopharynx whereas the rest showed a moderate to low level of expression. This is the first study to evaluate expression of virulence- and, colonization-related genes in the nasopharynx of healthy children and establishes the foundation for future gene expression studies during human pneumococcal disease.
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