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ABSTRACT: Activation of coagulation frequently occurs in severe infection and sepsis and may contribute to the development of thrombosis. Coagulation abnormalities in sepsis range from a small decrease in platelet count and subclinical prolongation of global clotting times to fulminant disseminated intravascular coagulation (DIC), characterized by simultaneous widespread microvascular thrombosis and profuse bleeding from various sites. Septic patients with severe forms of DIC may present with manifest thromboembolic disease or clinically less apparent microvascular fibrin deposition, which predominantly presents as multiple organ dysfunction. Thrombophilia is associated with a prohemostatic state and consequently with an increased tendency to develop thrombosis. Hypothetically, patients with thrombophilia may suffer from more severe coagulopathy in case of severe infection or sepsis, which may result in a more serious clinical course and an unfavorable outcome. On the basis of the knowledge of the pathogenesis of thrombosis in severe inflammation and sepsis, strategies aimed at the inhibition of coagulation activation have been developed and have been found favorable in experimental and clinical studies.
Seminars in Thrombosis and Hemostasis 04/2013; · 4.52 Impact Factor
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ABSTRACT: This Correspondence relates to the recently published article by Yan et al (Am J Pathol, 2012:420-430) that demonstrated that CCAAT/enhancer-binding protein δ (C/EBPδ) drives cytokine production, neutrophil accumulation, and lung vascular leakage in a murine model of lipopolysaccharide (LPS)-induced acute lung injury.
American Journal Of Pathology 04/2013; 182(4):1459-60. · 4.89 Impact Factor
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ABSTRACT: The gastrointestinal tract harbors a complex population of microbes that play a fundamental role in the development of the immune system and human health. Besides an important local contribution in the host defense against infections, it has become increasingly clear that intestinal bacteria also modulate immune responses at systemic sites. These new insights can be of profound clinical relevance especially for intensive care medicine where the majority of patients are treated with antibiotics, which have pervasive and long-term effects on the intestinal microbiota. Moreover, considerable progress has been made in defining the role of the intestinal microbiota in both health and disease. In this review, we highlight these aspects and focus on recent key findings addressing the role of intestinal microbiota in antimicrobial defense mechanisms and its impact on intestinal homeostasis in the critically ill.
Trends in Microbiology 02/2013; · 7.91 Impact Factor
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ABSTRACT: Intestinal colonization by antibiotic-resistant E. faecium is the first step in a process that can lead to infections in hospitalized patients. By comparative genome analysis and subsequent PCR screening we identified a locus, encoding a putative phosphotransferase system (PTS), that is widespread in isolates from hospital outbreaks (84.2%) and non-outbreak clinical infections (66.0%), but is absent from human commensal isolates. A deletion in this PTS significantly impaired the ability of E. faecium to colonize the murine intestinal tract during antibiotic treatment. This is the first description of a determinant that contributes to intestinal colonization in clinical E. faecium strains.
The Journal of Infectious Diseases 02/2013; · 6.41 Impact Factor
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ABSTRACT: Adenosine monophosphate-activated protein (AMP) activated kinase (AMPK) is a highly conserved kinase that plays a key role in energy homeostasis. Activation of AMPK was shown to reduce inflammation in response to lipolysaccharide in vitro and in vivo. 5-aminoimidazole-4-carbox-amide-1-β-D-ribofuranoside (AICAR) is intracellularly converted to the AMP analog ZMP, which activates AMPK. Lipoteichoic acid (LTA) is a major component of the cell wall of gram-positive bacteria that can trigger inflammatory responses. In contrast to lipopolysaccharide, little is known on effects of AMPK activation in LTA triggered innate immune responses. Here, we studied the potency of AMPK activation to reduce LTA-induced inflammation in vitro and in lungs in vivo. Activation of AMPK in vitro reduced cytokine production in the alveolar macrophage cell line MH-S. In vivo, AMPK activation reduced LTA-induced neutrophil influx, as well as protein leak and cytokine/chemokine levels in the bronchoalveolar space. In conclusion, AMPK activation inhibits LTA-induced lung inflammation in mice.
Journal of Biological Chemistry 01/2013; · 4.77 Impact Factor
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ABSTRACT: Critically ill patients frequently develop acute lung injury (ALI). Disturbed alveolar fibrin turnover, a characteristic feature of ALI, is the result of both activation of coagulation and inhibition of fibrinolysis. Nebulized fibrinolytic agents could exert lung-protective effects, via promotion of fibrinolysis as well as anti-inflammation.
Rats were challenged intratracheally with Pseudomonas aeruginosa, resulting in pneumonia as a model for direct ALI, or received an intravenous bolus infusion of lipopolysaccharide, as a model for indirect ALI. Rats were randomized to nebulization of normal saline (placebo), recombinant tissue plasminogen activator (rtPA), or monoclonal antibodies against plasminogen activator inhibitor-type 1 (anti-PAI-1).
Nebulized rtPA or anti-PA1-1 enhanced the bronchoalveolar fibrinolytic system, as reflected by a significant reduction of PAI-1 activity levels in bronchoalveolar lavage fluid, and a consequent increase in plasminogen activator activity (PAA) levels to supranormal values. Both treatments also significantly affected systemic fibrinolysis as reflected by a significant increase in PAA levels in plasma to supranormal levels. Neither nebulized rtPA nor anti-PA1-1 affected pulmonary inflammation. Neither treatment affected bacterial clearance of P. aeruginosa from the lungs in case of pneumonia.
Local treatment with rtPA or anti-PA1-1 affects pulmonary fibrinolysis but not inflammation in models of direct or indirect ALI in rats.
PLoS ONE 01/2013; 8(2):e55262. · 4.09 Impact Factor
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ABSTRACT: Interleukin-1 receptor like 1 (ST2) is a negative regulator of Toll-like receptor (TLR) signaling. TLRs are important for host defense during respiratory tract infections by both influenza and Streptococcus (S.) pneumoniae. Enhanced susceptibility to pneumococcal pneumonia is an important complication following influenza virus infection. We here sought to determine the role of ST2 in primary influenza A infection and secondary pneumococcal pneumonia. ST2 knockout (st2 -/-) and wild-type (WT) mice were intranasally infected with influenza A virus; in some experiments mice were infected 2 weeks later with S. pneumoniae. Both mouse strains cleared the virus similarly during the first 14 days of influenza infection and had recovered their weights equally at day 14. Overall st2-/- mice tended to have a stronger pulmonary inflammatory response upon infection with influenza; especially 14 days after infection modest but statistically significant elevations were seen in lung IL-6, IL-1β, KC, IL-10, and IL-33 concentrations and myeloperoxidase levels, indicative of enhanced neutrophil activity. Interestingly, bacterial lung loads were higher in st2-/- mice during the later stages of secondary pneumococcal pneumonia, which was associated with relatively increased lung IFN-γ levels. ST2 deficiency did not impact on gross lung pathology in either influenza or secondary S. pneumoniae pneumonia. These data show that ST2 plays a limited anti-inflammatory role during both primary influenza and postinfluenza pneumococcal pneumonia.
PLoS ONE 01/2013; 8(3):e58191. · 4.09 Impact Factor
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ABSTRACT: INTRODUCTION: Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. Protease-activated receptor-1 (PAR-1) is expressed by multiple cell types present in the lungs and can be activated by various proteases generated during acute inflammation. The cellular effect of PAR-1 activation partially depends on the specific protease involved. We here determined the role of PAR-1 in the host response during murine pneumococcal pneumonia. METHODS: Wild-type (WT) and PAR-1 knockout (KO) mice were infected intranasally with viable S. pneumoniae and observed in a survival study or euthanized at 6, 24 or 48 hours of infection. RESULTS: PAR-1 KO mice had a better survival early after infection compared to WT mice. Moreover, PAR-1 KO mice had lower bacterial loads in lungs and blood at 24 hours and in spleen and liver at 48 hours after infection. This favorable response was accompanied by lower lung histopathology scores and less neutrophil influx in PAR-1 KO mice. CONCLUSION: PAR-1 impairs host defense during murine pneumococcal pneumonia.
Critical care (London, England) 12/2012; 16(6):R238. · 4.61 Impact Factor
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J Daan de Boer,
Joris J T H Roelofs,
Alex F de Vos,
Regina de Beer,
Marcel Schouten,
Tijmen J Hommes,
Arie J Hoogendijk,
Onno J de Boer,
Ingrid Stroo,
Jaring S van der Zee,
Cornelis van 't Veer, Tom van der Poll
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ABSTRACT: Abstract The complex biology of asthma compels to use more relevant human allergens, such as house dust mite (HDM), to improve translation of animal models to human asthma. Lipopolysaccharide (LPS) exposure is associated with aggravation of asthma but mechanisms remain unclear. Here, we studied the effects of increasing LPS doses on HDM-evoked allergic lung inflammation. To this end mice were intranasally sensitized and challenged with HDM with or without increasing doses of LPS (0.001 - 10 µg). LPS dose-dependently inhibited HDM-induced eosinophil recruitment into the lungs and mucus production in the airways. LPS attenuated the production of Th2-cytokines (IL-4, IL-5, IL-10, IL-13) in HDM-challenged lungs, while enhancing HDM-induced release of IL-17, IL-33, IFN-γ and TNF-α. The shift towards a Th1 inflammatory response was further illustrated by a predominant neutrophilic lung inflammation after LPS administration at higher doses. LPS did not influence HDM-induced plasma IgE levels. While LPS did not significantly impact on activation of coagulation or complement in HDM-challenged lungs, it reduced HDM-initiated endothelial cell activation. This study is the first study to give insight in the effect of LPS in an allergic lung inflammation model making use of a clinically relevant allergen without systemic adjuvant, revealing that LPS dose-dependently inhibits HDM-induced pulmonary Th2 responses.
American Journal of Respiratory Cell and Molecular Biology 12/2012; · 5.13 Impact Factor
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ABSTRACT: Mounting evidence suggests an important role for CCAAT-enhancer binding protein delta (C/EBPδ) in the acute-phase response after bacterial infection. However, whether C/EBPδ limits pneumonia remains elusive and is the aim of this study. Therefore, bacterial outgrowth, inflammatory responses, inflammatory cell influx, and survival were assessed in wild-type and C/EBPδ(-/-) mice infected with Klebsiella pneumoniae via the airways. We showed that C/EBPδ expression is highly induced in the lung during pulmonary infection and that Klebsiella-induced mortality was significantly increased among C/EBPδ(-/-) mice. Bacterial loads and inflammatory responses were similar in wild-type and C/EBPδ(-/-) mice early during infection, whereas bacterial loads were increased in C/EBPδ(-/-) mice later during infection. Moreover, macrophage numbers were reduced in lungs of C/EBPδ(-/-) mice. In vitro experiments showed that C/EBPδ only slightly affects macrophage function. Our data thus show that C/EBPδ contributes to host defense against Klebsiella-induced pneumonia and suggests that C/EBPδ-dependent macrophage mobilization is a key mechanism.
The Journal of Infectious Diseases 11/2012; · 6.41 Impact Factor
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ABSTRACT: Intravenous administration of activated protein C (APC) inhibits coagulation and inflammation in the lungs of humans and animals. Investigations in rodents demonstrated that direct intrapulmonary delivery of APC also exerts anticoagulant and anti-inflammatory effects. The effect of intrabronchial administration of recombinant human (rh)APC on lipopolysaccharide (LPS)-induced hemostatic and inflammatory alterations in the bronchoalveolar space of humans was studied.Eight subjects received rhAPC via intrabronchial instillation by bronchoscope, while in a contralateral subsegment subjects received saline; all subjects were challenged bilaterally with LPS in the same lung subsegments. Four additional subjects received rhAPC (75 μg), with saline as control in the contralateral subsegment, while they were bilaterally "challenged" with saline. After 6 hours a bronchoalveolar lavage was performed and coagulation and inflammatory parameters were measured.rhAPC enhanced LPS-induced coagulation activation in the bronchoalveolar space, when compared with control side. In addition, rhAPC amplified LPS-induced proinflammatory responses, as indicated by higher concentrations of cytokines and chemokines. RhAPC alone did not have procoagulant or proinflammatory effects.Locally administered rhAPC has unexpected procoagulant and proinflammatory effects in LPS-challenged lung subsegments. These data argue against a role for intrapulmonary delivery of rhAPC as a treatment strategy for lung inflammatory disorders in humans. (ClinicalTrials.gov number: NCT00943267; Nederlands Trial register number: NTR1544).
European Respiratory Journal 10/2012; · 5.89 Impact Factor
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Ahmed Achouiti,
Thomas Vogl,
Constantin F Urban,
Marc Röhm,
Tijmen J Hommes,
Marieke A D van Zoelen,
Sandrine Florquin,
Johannes Roth,
Cornelis van 't Veer,
Alex F de Vos, Tom van der Poll
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ABSTRACT: Klebsiella (K.) pneumoniae is a common cause of pneumonia-derived sepsis. Myeloid related protein 8 (MRP8, S100A8) and MRP14 (S100A9) are the most abundant cytoplasmic proteins in neutrophils. They can form MRP8/14 heterodimers that are released upon cell stress stimuli. MRP8/14 reportedly exerts antimicrobial activity, but in acute fulminant sepsis models MRP8/14 has been found to contribute to organ damage and death. We here determined the role of MRP8/14 in K. pneumoniae sepsis originating from the lungs, using an established model characterized by gradual growth of bacteria with subsequent dissemination. Infection resulted in gradually increasing MRP8/14 levels in lungs and plasma. Mrp14 deficient (mrp14(-/-)) mice, unable to form MRP8/14 heterodimers, showed enhanced bacterial dissemination accompanied by increased organ damage and a reduced survival. Mrp14(-/-) macrophages were reduced in their capacity to phagocytose Klebsiella. In addition, recombinant MRP8/14 heterodimers, but not MRP8 or MRP14 alone, prevented growth of Klebsiella in vitro through chelation of divalent cations. Neutrophil extracellular traps (NETs) prepared from wildtype but not from mrp14(-/-) neutrophils inhibited Klebsiella growth; in accordance, the capacity of human NETs to kill Klebsiella was strongly impaired by an anti-MRP14 antibody or the addition of zinc. These results identify MRP8/14 as key player in protective innate immunity during Klebsiella pneumonia.
PLoS Pathogens 10/2012; 8(10):e1002987. · 9.13 Impact Factor
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ABSTRACT: Salmonella enterica infections result in diverse clinical manifestations. Typhoid fever, caused by S. enterica serovar Typhi (S. Typhi) and S. Paratyphi A, is a bacteremic illness but whose clinical features differ from other Gram-negative bacteremias. Non-typhoidal Salmonella (NTS) serovars cause self-limiting diarrhea with occasional secondary bacteremia. Primary NTS bacteremia can occur in the immunocompromised host and infants in sub-Saharan Africa. Recent studies on host-pathogen interactions in Salmonellosis using genome sequencing, murine models, and patient studies have provided new insights. The full genome sequences of numerous S. enterica serovars have been determined. The S. Typhi genome, compared to that of S. Typhimurium, harbors many inactivated or disrupted genes. This can partly explain the different immune responses both serovars induce upon entering their host. Similar genome degradation is also observed in the ST313 S. Typhimurium strain implicated in invasive infection in sub-Saharan Africa. Virulence factors, most notably, type III secretion systems, Vi antigen, lipopolysaccharide and other surface polysaccharides, flagella, and various factors essential for the intracellular life cycle of S. enterica have been characterized. Genes for these factors are commonly carried on Salmonella Pathogenicity Islands (SPIs). Plasmids also carry putative virulence-associated genes as well as those responsible for antimicrobial resistance. The interaction of Salmonella pathogen-associated molecular patterns (PAMPs) with Toll-like receptors (TLRs) and NOD-like receptors (NLRs) leads to inflammasome formation, activation, and recruitment of neutrophils and macrophages and the production of pro-inflammatory cytokines, most notably interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and interferon-gamma (IFN)-γ. The gut microbiome may be an important modulator of this immune response. S. Typhimurium usually causes a local intestinal immune response, whereas S. Typhi, by preventing neutrophil attraction resulting from activation of TLRs, evades the local response and causes systemic infection. Potential new therapeutic strategies may lead from an increased understanding of infection pathogenesis.
PLoS Pathogens 10/2012; 8(10):e1002933. · 9.13 Impact Factor
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ABSTRACT: Disseminated intravascular coagulation (DIC) is a syndrome characterized by systemic intravascular activation of coagulation, leading to widespread deposition of fibrin in the circulation. Recent knowledge on important pathogenetic mechanisms that may lead to DIC has resulted in novel preventive and therapeutic approaches to patients with DIC. The diagnosis of DIC can be made by sensitive laboratory tests; however, most of these tests are not readily available in a clinical setting. A reliable diagnosis can also be made on the basis of a small series of laboratory tests that can be combined in a scoring algorithm. The cornerstone of the management of DIC is the specific and vigorous treatment of the underlying disorder. Strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways.
Internal and Emergency Medicine 09/2012; · 2.06 Impact Factor
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ABSTRACT: The lectin-like domain of thrombomodulin (TM) plays an important regulatory role in sterile inflammatory conditions but its role in severe gram-positive infectious disease is unknown. Streptococcus (S.) pneumoniae is the most common cause of community-acquired pneumonia. The aim of this study was to determine the role of the lectin-like domain of TM in murine pneumococcal pneumonia.Wild-type (WT) and TM(LeD/LeD) mice (lacking the lectin-like domain of TM) were infected intranasally with viable S. pneumoniae and either observed in a survival study or euthanized 6, 24 or 48 hours after infection.TM(LeD/LeD) mice had a markedly better survival in pneumococcal pneumonia as compared to WT mice. At 48 hours post-infection with S. pneumoniae, TM(LeD/LeD) mice had lower bacterial loads in blood and liver, and exhibited less pulmonary inflammation as evidenced by less lung histopathology, less neutrophil influx and lower cytokine and chemokine levels. Plasma levels of pro-inflammatory cytokines were also reduced in TM(LeD/LeD) mice after exposure to the infection.Deletion of the lectin-like domain of TM improves the host defense in pneumococcal pneumonia. The lectin-like domain of TM may have a differential role in response to gram-positive or gram-negative bacteria.
European Respiratory Journal 08/2012; · 5.89 Impact Factor
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ABSTRACT: Lipopolysaccharide (LPS) is ubiquitous in the environment. Inhalation of LPS has been implicated in the pathogenesis and/or severity of several lung diseases, including pneumonia, chronic obstructive pulmonary disease and asthma. Alveolar macrophages are the main resident leukocytes exposed to inhaled antigens. To obtain insight into which innate immune pathways become activated within human alveolar macrophages upon exposure to LPS in vivo, we conducted a study in eight healthy humans, in which we instilled sterile saline into a lung segment by bronchoscope, followed by instillation of LPS into the contralateral lung. Six hours later a bilateral bronchoalveolar lavage was performed and whole-genome transcriptional profiling was done on purified alveolar macrophages, comparing cells exposed to saline or LPS from the same individuals. LPS induced differential expression of 2932 genes in alveolar macrophages; 1520 genes were upregulated, whereas 1440 genes were downregulated. Twenty-six biological functions were overrepresented in LPS exposed macrophages, Forty-four canonical pathways affected by LPS were identified, among which the genes associated with the role of pattern recognition receptors in recognition of bacteria and viruses represented the top pathway. Other pathways included cellular immune response, signaling by tumor necrosis factor (receptor) family members, cytokine signaling and glucocorticoid receptor signaling. These results reveal for the first time a large number of functional pathways influenced by the biologically relevant challenge provided by LPS administered into the airways. These data can assist in identifying novel targets for therapeutic intervention in pulmonary diseases associated with LPS exposure, including pneumonia, asthma and chronic obstructive pulmonary disease.
Molecular Medicine 08/2012; · 3.76 Impact Factor
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ABSTRACT: Background. Pneumonia is frequently caused by gram-negative pathogens, among which Klebsiella pneumoniae prominently features. Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is important for an appropriate immune response during infection. TLR signaling can proceed via 2 distinct routes that are dependent on the adaptor proteins Myeloid differentiation primary response gene (88) (MyD88) and TIR-domain-containing adaptor-inducing interferon-β (TRIF). The aim of the study was to determine the relative contribution of MyD88 and TRIF signaling in resident and hematopoietic cells to host defense during pneumonia. Methods. Bone marrow chimeras of MyD88 deficient/wild type and TRIF mutant/wild type mice were created and infected with K. pneumoniae via the airways. Results. MyD88 in both resident and hematopoietic cells contributed to survival and antibacterial defense in late-stage infection, whereas only TRIF in hematopoietic cells was protective. On the other hand, resident MyD88 and hematopoietic TRIF contributed to distant cellular injury. Resident MyD88 was pivotal for early chemokine release and neutrophil recruitment in the bronchoalveolar space. Conclusions. MyD88- and TRIF-dependent signaling has a differential contribution to host defense in different cell types that changes from early- to late-stage gram-negative pneumonia.
The Journal of Infectious Diseases 08/2012; 206(9):1415-23. · 6.41 Impact Factor
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ABSTRACT: Mechanical ventilation (MV) has the potential to induce lung damage in healthy lungs or aggravate existing lung injury. Polymorphonuclear neutrophil (PMN) recruitment plays an important role in driving the inflammatory response in ventilator-induced lung injury (VILI). The cyclin-dependent kinase inhibitor r-roscovitine has been shown to induce apoptosis in PMNs. In this study, we investigated the potential of r-roscovitine treatment in reducing lung damage in a mouse model of VILI. Mice were tracheotomized and subjected to lung-protective MV with lower (∼7.5 mL/kg) or lung-injurious MV with higher (∼15 mL/kg) tidal volume (VT). R-roscovitine treatment enhanced apoptosis in PMNs in vitro. Ventilator-induced lung injury was associated with pulmonary PMN influx in low and high VT MV. During lung-injurious MV, r-roscovitine treatment reduced the number of PMNs and lowered levels of the lung damage markers RAGE (receptor for advanced glycation end products) and total immunoglobulin M in bronchoalveolar lavage fluid. R-roscovitine did not affect cytokine or chemokine levels in the bronchoalveolar space, neither during lung-protective nor lung-injurious MV. Thus, r-roscovitine treatment reduces lung damage in VILI, possibly dependent on increased apoptosis of PMNs.
Shock (Augusta, Ga.) 07/2012; 38(4):375-80. · 2.87 Impact Factor
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ABSTRACT: BACKGROUND: Asplenic individuals are susceptible for overwhelming infection with Streptococcus pneumoniae, carrying a high mortality. Although Toll-like receptor (TLR)-2 is considered the major receptor for Gram-positive bacteria in innate immunity, it does not play a major role in host defense against pneumococcal pneumonia. We wanted to investigate if in absence of an intact spleen as a first line of defense, the role of TLR2 during pneumococcal pneumonia becomes more significant, thereby explaining its insignificant role during infections in immune competent hosts. METHODS: We intranasally infected splenectomized wildtype (WT), TLR2 knock-out (KO) and TLR2/4 double KO mice with either serotype 2 or 3 S. pneumoniae. RESULTS: There were no differences between asplenic WT and TLR2KO mice of bacterial loads in lung homogenates and blood, cytokine and chemokine levels in the lungs, and lung pathology scores. TLR2/4 double KO mice were not impaired in bacterial control as well, which indicates that besides the interaction between S. pneumoniae and TLR2, the interaction between pneumolysin and TLR4 does not stimulate antibacterial defense in the asplenic host either. CONCLUSIONS: These results argue against a significant role of TLR2 in host defense during S. pneumoniae pneumonia in the asplenic state. Therefore, other components can provide sufficient backup mechanisms for TLR2 deficiency in the defense against intrapulmonary infections with S. pneumoniae of the otherwise immune competent host.
BMC Infectious Diseases 06/2012; 12(1):139. · 3.12 Impact Factor
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ABSTRACT: Pneumonia is a common cause of morbidity and mortality and the most frequent source of sepsis. Bacteria that try to invade normally sterile body sites are recognized by innate immune cells through pattern recognition receptors, among which toll-like receptors (TLRs) feature prominently. Interleukin-1 receptor (IL-1R)-associated kinase (IRAK)-M is a proximal inhibitor of TLR signaling expressed by epithelial cells and macrophages in the lung. To determine the role of IRAK-M in host defense against bacterial pneumonia, IRAK-M-deficient (IRAK-M(-/-)) and normal wild-type (WT) mice were infected intranasally with Klebsiella pneumoniae. IRAK-M mRNA was upregulated in lungs of WT mice with Klebsiella pneumonia, and the absence of IRAK-M resulted in a strongly improved host defense as reflected by reduced bacterial growth in the lungs, diminished dissemination to distant body sites, less peripheral tissue injury and better survival rates. Although IRAK-M(-/-) alveolar macrophages displayed enhanced responsiveness toward intact K. pneumoniae and Klebsiella lipopolysaccharide (LPS) in vitro, IRAK-M(-/-) mice did not show increased cytokine or chemokine levels in their lungs after infection in vivo. The extent of lung inflammation was increased in IRAK-M(-/-) mice shortly after K. pneumoniae infection, as determined by semiquantitative scoring of specific components of the inflammatory response in lung tissue slides. These data indicate that IRAK-M impairs host defense during pneumonia caused by a common gram-negative respiratory pathogen.
Molecular Medicine 06/2012; 18(1):1067-75. · 3.76 Impact Factor
