Dataset Information

CpG-ODN and MPLA prevent mortality in a murine model of post-hemorrhage-Staphyloccocus aureus pneumonia.

ABSTRACT: Infections are the most frequent cause of complications in trauma patients. Post-traumatic immune suppression (IS) exposes patients to pneumonia (PN). The main pathogen involved in PN is Methicillin Susceptible Staphylococcus aureus (MSSA). Dendritic cells () may be centrally involved in the IS. We assessed the consequences of hemorrhage on pneumonia outcomes and investigated its consequences on DCs functions. A murine model of hemorrhagic shock with a subsequent MSSA pneumonia was used. Hemorrhage decreased the survival rate of infected mice, increased systemic dissemination of sepsis and worsened inflammatory lung lesions. The mRNA expression of Tumor Necrosis Factor-alpha (TNF-?), Interferon-beta (IFN-?) and Interleukin (IL)-12p40 were mitigated for hemorrhaged-mice. The effects of hemorrhage on subsequent PN were apparent on the pDCs phenotype (reduced MHC class II, CD80, and CD86 molecule membrane expression). In addition, hemorrhage dramatically decreased CD8(+) cDCs- and CD8(-) cDCs-induced allogeneic T-cell proliferation during PN compared with mice that did not undergo hemorrhage. In conclusion, hemorrhage increased morbidity and mortality associated with PN; induced severe phenotypic disturbances of the pDCs subset and functional alterations of the cDCs subset. After hemorrhage, a preventive treatment with CpG-ODN or Monophosphoryl Lipid A increased transcriptional activity in DCs (TNF-?, IFN-? and IL-12p40) and decreased mortality of post-hemorrhage MSSA pneumonia.

SUBMITTER: Roquilly A

PROVIDER: S-EPMC2951351 | biostudies-other | 2010

REPOSITORIES: biostudies-other

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CpG-ODN and MPLA prevent mortality in a murine model of post-hemorrhage-Staphyloccocus aureus pneumonia.

Roquilly Antoine A Gautreau Laetitia L Segain Jean Pierre JP de Coppet Pierre P Sebille Véronique V Jacqueline Cédric C Caillon Jocelyne J Potel Gilles G Lejus Corinne C Josien Régis R Asehnoune Karim K

PloS one 20101007 10

Infections are the most frequent cause of complications in trauma patients. Post-traumatic immune suppression (IS) exposes patients to pneumonia (PN). The main pathogen involved in PN is Methicillin Susceptible Staphylococcus aureus (MSSA). Dendritic cells () may be centrally involved in the IS. We assessed the consequences of hemorrhage on pneumonia outcomes and investigated its consequences on DCs functions. A murine model of hemorrhagic shock with a subsequent MSSA pneumonia was used. Hemorrh ...[more]

PMID: 20949109

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Project description:Rationale: Antimicrobial resistance challenges therapy of pneumonia. Enhancing macrophage microbicidal responses would combat this problem but is limited by our understanding of how alveolar macrophages (AMs) kill bacteria. Objectives: To define the role and mechanism of AM apoptosis-associated bacterial killing in the lung. Methods: We generated a unique CD68.hMcl-1 transgenic mouse with macrophage-specific overexpression of the human antiapoptotic Mcl-1 protein, a factor upregulated in AMs from patients at increased risk of community-acquired pneumonia, to address the requirement for apoptosis-associated killing. Measurements and Main Results: Wild-type and transgenic macrophages demonstrated comparable ingestion and initial phagolysosomal killing of bacteria. Continued ingestion (for ≥12 h) overwhelmed initial killing, and a second, late-phase microbicidal response killed viable bacteria in wild-type macrophages, but this response was blunted in CD68.hMcl-1 transgenic macrophages. The late phase of bacterial killing required both caspase-induced generation of mitochondrial reactive oxygen species and nitric oxide, the peak generation of which coincided with the late phase of killing. The CD68.hMcl-1 transgene prevented mitochondrial reactive oxygen species but not nitric oxide generation. Apoptosis-associated killing enhanced pulmonary clearance of Streptococcus pneumoniae and Haemophilus influenzae in wild-type mice but not CD68.hMcl-1 transgenic mice. Bacterial clearance was enhanced in vivo in CD68.hMcl-1 transgenic mice by reconstitution of apoptosis with BH3 mimetics or clodronate-encapsulated liposomes. Apoptosis-associated killing was not activated during Staphylococcus aureus lung infection. Conclusions: Mcl-1 upregulation prevents macrophage apoptosis-associated killing and establishes that apoptosis-associated killing is required to allow AMs to clear ingested bacteria. Engagement of macrophage apoptosis should be investigated as a novel, host-based antimicrobial strategy.

Project description:Pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) is a significant cause of morbidity and mortality in infants particularly following lower respiratory tract viral infections such as Respiratory Syncytial Virus (RSV). However, the mechanisms by which co-infection of infants by MRSA and RSV cause increased lung pathology are unknown. Because the infant immune system is qualitatively and quantitatively different from adults we developed a model of infant MRSA pneumonia which will allow us to investigate the effects of RSV co-infection on disease severity. We infected neonatal and adult mice with increasing doses of MRSA and demonstrate that neonatal mice have delayed kinetics in clearing the bacteria in comparison to adult mice. There were differences in recruitment of immune cells into the lung following infection. Adult mice exhibited an increase in neutrophil recruitment that coincided with reduced bacterial titers followed by an increase in macrophages. Neonatal mice, however, exhibited an early increase in neutrophils that did not persist despite continued presence of the bacteria. Unlike the adult mice, neonatal mice failed to exhibit an increase in macrophages. Neonates exhibited a decrease in phagocytosis of MRSA suggesting that the decrease in clearance was partially due to deficient phagocytosis of the bacteria. Both neonates and adults responded with an increase in pro-inflammatory cytokines following infection. However, in contrast to the adult mice, neonates did not express constitutive levels of the anti-microbial peptide Reg3γ in the lung. Infection of neonates did not stimulate expression of the co-stimulatory molecule CD86 by dendritic cells and neonates exhibited a diminished T cell response compared to adult mice. Overall, we have developed a neonatal model of MRSA pneumonia that displays a similar delay in bacterial clearance as is observed in the neonatal intensive care unit and will be useful for performing co-infection studies.

Project description:Stroke outcome studies often combine cases of intracerebral hemorrhage (ICH) and ischemic stroke (IS). These studies of mixed stroke typically ignore computed tomography (CT) findings for ICH cases, though the impact of omitting these traditional predictors of ICH mortality is unknown. We investigated the incremental impact of ICH CT findings on mortality prediction model performance.Cases of ICH and IS (2000-2003) were identified from the Brain Attack Surveillance in Corpus Christi (BASIC) project. Base models predicting 30-day mortality included demographics, stroke type, and clinical findings (National Institutes of Health Stroke Scale (NIHSS) +/- Glasgow Coma Scale (GCS)). The impact of adding CT data (volume, intraventricular hemorrhage, infratentorial location) was assessed with the area under the curve (AUC), unweighted sum of squared residuals (?), and integrated discrimination improvement (IDI). The model assessment was performed first for the mixed case of IS and ICH, and then repeated for ICH cases alone to determine whether any lack of improvement in model performance with CT data for mixed stroke type was due to IS cases naturally forming a larger proportion of the total sample than ICH.A total of 1,256 cases were included (86% IS, 14% ICH). Thirty-day mortality was 16% overall (11% for IS; 43% for ICH). When both clinical scales (NIHSS and GCS) were included, none of the model performance measures showed improvement with the addition of CT findings whether considering IS and ICH together (?AUC: 0.002, 95% CI -0.01, 0.02; ??: -3.0, 95% CI -9.1, 2.6; IDI: 0.017, 95% CI -0.004, 0.05) or considering ICH cases alone (?AUC: 0.02, 95% CI -0.02, 0.08; ??: -2.0, 95% CI -9.7, 3.4; IDI 0.065, 95% CI -0.03, 0.21). If NIHSS was the only clinical scale included, there was still no improvement in AUC or ? when CT findings were added for the sample with IS/ICH combined (?AUC: 0.005, 95% CI -0.01, 0.02; ??: -5.0, 95% CI -11.6, 1.0) or for ICH cases alone (?AUC: 0.05, 95% CI -0.002, 0.11; ??: -4.2, 95% CI -11.5, 2.3). However, IDI was improved when NIHSS was the only clinical scale for IS/ICH combined (IDI: 0.029, 95% CI 0.002, 0.065) and ICH alone (IDI: 0.12, 95% CI 0.005, 0.26).Excluding ICH CT findings had only minimal impact on mortality prediction model performance whether examining ICH and IS together or ICH alone. These findings have important implications for the design of clinical studies involving ICH patients.

Dataset Information

CpG-ODN and MPLA prevent mortality in a murine model of post-hemorrhage-Staphyloccocus aureus pneumonia.

Publications

CpG-ODN and MPLA prevent mortality in a murine model of post-hemorrhage-Staphyloccocus aureus pneumonia.

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