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Moranta D.,Program Infection and Immunity | Moranta D.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | Regueiro V.,Program Infection and Immunity | Regueiro V.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | And 11 more authors.
Infection and Immunity | Year: 2010

Human β-defensins (hBDs) contribute to the protection of the respiratory tract against pathogens. It is reasonable to postulate that pathogens have developed countermeasures to resist them. Klebsiella pneumoniae capsule polysaccharide (CPS), but not the lipopolysaccharide O antigen, mediated resistance against hBD1 and hBD2. hBD3 was the most potent hBD against Klebsiella. We investigated the possibility that as a strategy for survival in the lung, K. pneumoniae may not activate the expression of hBDs. Infection of A549 and normal human bronchial cells with 52145-ΔwcaK2, a CPS mutant, increased the expression of hBD2 and hBD3. Neither the wild type nor the lipopolysaccharide O antigen mutant increased the expression of hBDs. In vivo, 52145-ΔwcaK2 induced higher levels of mBD4 and mBD14, possible mouse orthologues of hBD2 and hBD3, respectively, than the wild type. 52145-ΔwcaK2-dependent upregulation of hBD2 occurred via NF-κB and mitogen-activated protein kinases (MAPKs) p44/42, Jun N-terminal protein kinase (JNK)-dependent pathways. The increase in hBD3 expression was dependent on the MAPK JNK. 52145-ΔwcaK2 engaged Toll-like receptors 2 and 4 (TLR2 and TLR4) to activate hBD2, whereas hBD3 expression was dependent on NOD1. K. pneumoniae induced the expression of CYLD and MKP-1, which act as negative regulators for 52145-ΔwcaK2-induced expression of hBDs. Bacterial engagement of pattern recognition receptors induced CYLD and MKP-1, which may initiate the attenuation of proinflammatory pathways. The results of this study indicate that K. pneumoniae CPS not only protects the pathogen from the bactericidal action of defensins but also impedes their expression. These features of K. pneumoniae CPS may facilitate pathogen survival in the hostile environment of the lung. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Lopez-Rojas R.,University of Seville | Lopez-Rojas R.,Hospitales Universitarios Virgen Del Rocio | Docobo-Perez F.,University of Seville | Pachon-Ibanez M.E.,University of Seville | And 7 more authors.
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2011

Pan-resistant Acinetobacter baumannii have prompted the search for therapeutic alternatives. We evaluate the efficacy of four cecropin A-melittin hybrid peptides (CA-M) in vivo. Toxicity was determined in mouse erythrocytes and in mice (lethal dose parameters were LD0, LD50, LD100). Protective dose 50 (PD50) was determined by inoculating groups of ten mice with the minimal lethal dose of A. baumannii (BMLD) and treating with doses of each CA-M from 0.5 mg/kg to LD0. The activity of CA-Ms against A. baumannii was assessed in a peritoneal sepsis model. Mice were sacrificed at 0 and 1, 3, 5, and 7-h post-treatment. Spleen and peritoneal fluid bacterial concentrations were measured. CA(1-8)M(1-18) was the less haemolytic on mouse erythrocytes. LD0 (mg/kg) was 32 for CA(1-8)M(1-18), CA(1-7)M(2-9), and Oct-CA(1-7)M(2-9), and 16 for CA(1-7)M(5-9). PD50 was not achieved with non-toxic doses (≤LD0). In the sepsis model, all CA-Ms were bacteriostatic in spleen, and decreased bacterial concentration (p<0.05) in peritoneal fluid, at 1-h post-treatment; at later times, bacterial regrowth was observed in peritoneal fluid. CA-Ms showed local short-term efficacy in the peritoneal sepsis model caused by pan-resistant Acinetobacter baumannii. © 2011 Springer-Verlag.


Cilloniz C.,University of Barcelona | Cilloniz C.,Research Center Biomedica En Red Enfermedades Respiratorias CibeRes | Ewig S.,Thoraxzentrum Ruhrgebiet | Menendez R.,Research Center Biomedica En Red Enfermedades Respiratorias CibeRes | And 13 more authors.
Journal of Infection | Year: 2012

Background: Bacterial co-infection is an important contributor to morbidity and mortality during influenza pandemics .We investigated the incidence, risk factors and outcome of patients with influenza A H1N1 pneumonia and bacterial co-infection. Methods: Prospective observational study of consecutive hospitalized patients with influenza A H1N1 virus and community-acquired pneumonia (CAP). We compared cases with and without bacterial co-infection. Results: The incidence of influenza A H1N1 infection in CAP during the pandemic period was 19% (. n, 667). We studied 128 patients; 42(33%) had bacterial co-infection. The most frequently isolated bacterial pathogens were . Streptococcus pneumoniae (26, 62%) and . Pseudomonas aeruginosa (6, 14%). Predictors for bacterial co-infection were chronic obstructive pulmonary disease (COPD) and increase of platelets count. The hospital mortality was 9%. Factors associated with mortality were age ≥65 years, presence of septic shock and the need for mechanical ventilation. Although patients with bacterial co-infection presented with higher Pneumonia Severity Index risk class, hospital mortality was similar to patients without bacterial co-infection (7% . vs. 11%, respectively, . p = 0.54). Conclusion: Bacterial co-infection was frequent in influenza A H1N1 pneumonia, with COPD and increased platelet count as the main predictors. Although associated with higher severe scales at admission, bacterial co-infection did not influence mortality of these patients. © 2012 The British Infection Association.


Cilloniz C.,University of Barcelona | Cilloniz C.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | Ewig S.,Thoraxzentrum Ruhrgebiet | Polverino E.,University of Barcelona | And 13 more authors.
European Respiratory Journal | Year: 2012

The purpose of this study was to establish the microbial aetiology and outcomes of patients with community-acquired pneumonia (CAP) treated as outpatients after presenting to a hospital emergency care unit. A prospective observational study was carried out in the Hospital Clinic of Barcelona (Barcelona, Spain). All consecutive cases of CAP treated as outpatients were included. 568 adult outpatients with CAP were studied (mean±SD age 47.2±17.6 yrs; 110 (19.4%) were aged o65 yrs). Aetiological diagnoses were established in 188 (33.1%) cases. Streptococcus pneumoniae was the most frequent pathogen followed by Mycoplasma pneumoniae and respiratory viruses. Legionella was detected in 13 (2.3%) cases. More than one causative agent was found in 17 (9.0%) patients. Mortality was low (three (0.5%) patients died) and other adverse events were rare (30 (5.2%) patients had complications, 13 (2.3%) were re-admitted and treatment failed in 13 (2.3%)). Complications were mostly related to pleural effusion and empyema, and readmissions and treatment failures to comorbidities. Outpatients with CAP have a characteristic microbial pattern. Regular antipneumococcal coverage remains mandatory. Treatment failures and re-admissions are rare and may be reduced by increased attention to patients requiring short-term observation in the emergency care unit and in the presence of pleural effusion and comorbidities. Copyright©ERS 2012.


PubMed | University of Barcelona, Hospital Clinic of Barcelona, Research Center Biomedica En Red Enfermedades Respiratorias CibeRes and New York Presbyterian Weill Cornell Medical Center
Type: | Journal: The Journal of infection | Year: 2017

A subgroup of patients admitted to the hospital with a diagnosis of community-acquired pneumonia (CAP) have received antibiotic therapy prior to admission for the current episode of pneumonia. The objective of this study was to assess the clinical course of patients receiving antibiotics prior to admission, compared to patients not previously treated. An observational cohort of 3,364 CAP patients consecutively admitted to our hospital, and prospectively included, were studied. We collected clinical, microbiological and biochemical parameters, focusing on recent antibiotics received prior to admission. 610 (18%) patients received antibiotics prior to hospital admission for the current CAP episode. Patients with previous antibiotic use developed septic shock less frequently (4% vs. 7%, p=0.007) and required invasive ventilation less often (3% vs. 6%, p=0.002). After adjustment by different covariate factors and propensity score, antibiotic therapy was still independently associated with a lower incidence of septic shock at admission (OR 0.54 [95% CI 0.31-0.95], p=0.03) and less need for invasive ventilation (OR 0.38 [95% CI 0.16-0.91], p=0.03). In this cohort, recent use of antibiotics before hospital admission in CAP seems to be associated with a lower incidence of septic shock on admission and a lower need for invasive ventilation.


Lery L.M.S.,Institute Pasteur Paris | Lery L.M.S.,French Institute of Health and Medical Research | Lery L.M.S.,Federal University of Rio de Janeiro | Frangeul L.,Institute Pasteur Paris | And 20 more authors.
BMC Biology | Year: 2014

Background: Klebsiella pneumoniae strains are pathogenic to animals and humans, in which they are both a frequent cause of nosocomial infections and a re-emerging cause of severe community-acquired infections. K. pneumoniae isolates of the capsular serotype K2 are among the most virulent. In order to identify novel putative virulence factors that may account for the severity of K2 infections, the genome sequence of the K2 reference strain Kp52.145 was determined and compared to two K1 and K2 strains of low virulence and to the reference strains MGH 78578 and NTUH-K2044.Results: In addition to diverse functions related to host colonization and virulence encoded in genomic regions common to the four strains, four genomic islands specific for Kp52.145 were identified. These regions encoded genes for the synthesis of colibactin toxin, a putative cytotoxin outer membrane protein, secretion systems, nucleases and eukaryotic-like proteins. In addition, an insertion within a type VI secretion system locus included sel1 domain containing proteins and a phospholipase D family protein (PLD1). The pld1 mutant was avirulent in a pneumonia model in mouse. The pld1 mRNA was expressed in vivo and the pld1 gene was associated with K. pneumoniae isolates from severe infections. Analysis of lipid composition of a defective E. coli strain complemented with pld1 suggests an involvement of PLD1 in cardiolipin metabolism.Conclusions: Determination of the complete genome of the K2 reference strain identified several genomic islands comprising putative elements of pathogenicity. The role of PLD1 in pathogenesis was demonstrated for the first time and suggests that lipid metabolism is a novel virulence mechanism of K. pneumoniae. © 2014 Lery et al.; licensee BioMed Central Ltd.


Prina E.,University of Barcelona | Ceccato A.,University of Barcelona | Ceccato A.,Hospital Nacional Alejandro Posadas | Torres A.,University of Barcelona | And 2 more authors.
Critical Care | Year: 2016

Despite improvements in the management of community-acquired pneumonia (CAP), morbidity and mortality are still high, especially in patients with more severe disease. Early and appropriate antibiotics remain the cornerstone in the treatment of CAP. However, two aspects seem to contribute to a worse outcome: an uncontrolled inflammatory reaction and an inadequate immune response. Adjuvant treatments, such as corticosteroids and intravenous immunoglobulins, have been proposed to counterbalance these effects. The use of corticosteroids in patients with severe CAP and a strong inflammatory reaction can reduce the time to clinical stability, the risk of treatment failure, and the risk of progression to acute respiratory distress syndrome. The administration of intravenous immunoglobulins seems to reinforce the immune response to the infection in particular in patients with inadequate levels of antibodies and when an enriched IgM preparation has been used; however, more studies are needed to determinate their impact on outcome and to define the population that will receive more benefit. © 2016 Prina et al.


Prina E.,University of Barcelona | Prina E.,Instituto Of Ricovero E Cura A Carattere Scientifico Fondazione Ca Granda | Ferrer M.,University of Barcelona | Ferrer M.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | And 15 more authors.
Chest | Year: 2013

Background: Thrombocytosis, often considered a marker of normal inflammatory reaction of infections, has been recently associated with increased mortality in hospitalized patients with communityacquired pneumonia (CAP). We assessed the characteristics and outcomes of patients with CAP and thrombocytosis (platelet count ≥ 4 × 105/mm3) compared with thrombocytopenia (platelet count, 105/mm3) and normal platelet count. Methods: We prospectively analyzed 2,423 consecutive, hospitalized patients with CAP. We excluded patients with immunosuppression, neoplasm, active TB, or hematologic disease. Results: Fifty-three patients (2%) presented with thrombocytopenia, 204 (8%) with thrombocytosis, and 2,166 (90%) had normal platelet counts. Patients with thrombocytosis were younger (P < .001); those with thrombocytopenia more frequently had chronic heart and liver disease (P < .001 for both). Patients with thrombocytosis presented more frequently with respiratory complications, such as complicated pleural effusion and empyema (P < .001), whereas those with thrombocytopenia presented more often with severe sepsis (P < .001), septic shock (P = .009), need for invasive mechanical ventilation (P < .001), and ICU admission (P = .011). Patients with thrombocytosis and patients with thrombocytopenia had longer hospital stays (P = .004), and higher 30-day mortality (P = .001) and readmission rates (P = .011) than those with normal platelet counts. Multivariate analysis confirmed a significant association between thrombocytosis and 30-day mortality (OR, 2.720; 95% CI, 1.589-4.657; P < .001). Adding thrombocytosis to the confusion, respiratory rate, and BP plus age ≥65 years score slightly improved the accuracy to predict mortality (area under the receiver operating characteristic curve increased from 0.634 to 0.654, P = .049). Conclusions: Thrombocytosis in patients with CAP is associated with poor outcome, complicated pleural effusion, and empyema. The presence of thrombocytosis in CAP should encourage ruling out respiratory complication and could be considered for severity evaluation. © 2013 American College of Chest Physicians.


March C.,Laboratory Microbial Pathogenesis | March C.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | Cano V.,Laboratory Microbial Pathogenesis | Cano V.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | And 14 more authors.
PLoS ONE | Year: 2013

Phagocytosis is a key process of the immune system. The human pathogen Klebsiella pneumoniae is a well known example of a pathogen highly resistant to phagocytosis. A wealth of evidence demonstrates that the capsule polysaccharide (CPS) plays a crucial role in resistance to phagocytosis. The amoeba Dictyostelium discoideum shares with mammalian macrophages the ability to phagocytose and kill bacteria. The fact that K. pneumoniae is ubiquitous in nature and, therefore, should avoid predation by amoebae, poses the question whether K. pneumoniae employs similar means to counteract amoebae and mammalian phagocytes. Here we developed an assay to evaluate K. pneumoniae-D. discoideum interaction. The richness of the growth medium affected the threshold at which the cps mutant was permissive for Dictyostelium and only at lower nutrient concentrations the cps mutant was susceptible to predation by amoebae. Given the critical role of bacterial surface elements on host-pathogen interactions, we explored the possible contribution of the lipopolysaccharide (LPS) and outer membrane proteins (OMPs) to combat phagoyctosis by D. discoideum. We uncover that, in addition to the CPS, the LPS O-polysaccharide and the first core sugar participate in Klebsiella resistance to predation by D. discoideum. K. pneumoniae LPS lipid A decorations are also necessary to avoid predation by amoebae although PagP-dependent palmitoylation plays a more important role than the lipid A modification with aminoarabinose. Mutants lacking OMPs OmpA or OmpK36 were also permissive for D. discoideium growth. Except the LPS O-polysaccharide mutants, all mutants were more susceptible to phagocytosis by mouse alveolar macrophages. Finally, we found a correlation between virulence, using the pneumonia mouse model, and resistance to phagocytosis. Altogether, this work reveals novel K. pneumoniae determinants involved in resistance to phagocytosis and supports the notion that Dictyostelium amoebae might be useful as host model to measure K. pneumoniae virulence and not only phagocytosis. © 2013 March et al.


Rinaudo M.,University of Barcelona | Ferrer M.,University of Barcelona | Ferrer M.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | Terraneo S.,University of Barcelona | And 10 more authors.
Chest | Year: 2015

BACKGROUND: COPD seems related to poor outcome in patients with ventilator-associated pneumonia (VAP). However, many patients in the ICU with COPD do not require intubation but can also develop pneumonia in the ICU. We, therefore, compared the characteristics and outcomes of patients with ICU-acquired pneumonia (ICUAP) with and without underlying COPD. METHODS: We prospectively assessed the characteristics, microbiology, systemic inflammatory response, and survival of 279 consecutive patients with ICUAP clustered according to underlying COPD or not. The primary end point was 90-day survival. RESULTS: Seventy-one patients (25%) had COPD. The proportion of VAP was less frequent in patients with COPD: 30 (42%) compared with 126 (61%) in patients without COPD ( P = .011). Patients with COPD were older; were more frequently men, smokers, and alcohol abusers; and more frequently had previous use of noninvasive ventilation. The rate of microbiologic diagnosis was similar between groups, with a higher rate of Aspergillus species and a lower rate of Enterobacteriaceae in patients with COPD. We found lower levels of IL-6 and IL-8 in patients with COPD without previous intubation. The 90-day mortality was higher in patients with COPD (40 [57%] vs 74 [37%] in patients without COPD, P = .003). Among others, COPD was independently associated with decreased 90-day survival in the overall population (adjusted hazard ratio, 1.94; 95% CI, 1.11-3.40; P = .020); this association was observed only in patients with VAP but not in those without previous intubation. CONCLUSIONS: COPD was independently associated with decreased 90-day survival in patients with VAP but not in those without previous intubation. © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS.

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