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Imaging of disease dynamics during meningococcal sepsis.

ABSTRACT: Neisseria meningitidis is a human pathogen that causes septicemia and meningitis with high mortality. The disease progression is rapid and much remains unknown about the disease process. The understanding of disease development is crucial for development of novel therapeutic strategies and vaccines against meningococcal disease. The use of bioluminescent imaging combined with a mouse disease model allowed us to investigate the progression of meningococcal sepsis over time. Injection of bacteria in blood demonstrated waves of bacterial clearance and growth, which selected for Opa-expressing bacteria, indicating the importance of this bacterial protein. Further, N. meningitidis accumulated in the thyroid gland, while thyroid hormone T4 levels decreased. Bacteria reached the mucosal surfaces of the upper respiratory tract, which required expression of the meningococcal PilC1 adhesin. Surprisingly, PilC1 was dispensable for meningococcal growth in blood and for crossing of the blood-brain barrier, indicating that the major role of PilC1 is to interact with mucosal surfaces. This in vivo study reveals disease dynamics and organ targeting during meningococcal disease and presents a potent tool for further investigations of meningococcal pathogenesis and vaccines in vivo. This might lead to development of new strategies to improve the outcome of meningococcal disease in human patients.

SUBMITTER: Sjolinder H

PROVIDER: S-EPMC1797199 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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Imaging of disease dynamics during meningococcal sepsis.

Sjölinder Hong H Jonsson Ann-Beth AB

PloS one 20070221 2

Neisseria meningitidis is a human pathogen that causes septicemia and meningitis with high mortality. The disease progression is rapid and much remains unknown about the disease process. The understanding of disease development is crucial for development of novel therapeutic strategies and vaccines against meningococcal disease. The use of bioluminescent imaging combined with a mouse disease model allowed us to investigate the progression of meningococcal sepsis over time. Injection of bacteria ...[more]

PMID: 17311106

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Project description:BackgroundNeisseria meningitidis (Nm) is the cause of epidemic meningitis and fulminant meningococcal septicemia. The clinical presentations and outcome of meningococcal septic shock is closely related to the circulating levels of lipopolysaccharides (LPS) and of Neisseria meningitidis DNA (Nm DNA). We have previously explored the distribution of Nm DNA in tissues from large organs of patients dying of meningococcal septic shock and in a porcine meningococcal septic shock model.Objective1) To explore the feasibility of measuring LPS levels in tissues from the large organs in patients with meningococcal septic shock and in a porcine meningococcal septic shock model. 2) To evaluate the extent of contamination of non-specific LPS during the preparation of tissue samples.Patients and methodsPlasma, serum, and fresh frozen (FF) tissue samples from the large organs of three patients with lethal meningococcal septic shock and two patients with lethal pneumococcal disease. Samples from a porcine meningococcal septic shock model were included. Frozen tissue samples were thawed, homogenized, and prepared for quantification of LPS by Pyrochrome® Limulus Amoebocyte Lysate (LAL) assay.ResultsN. meningitidis DNA and LPS was detected in FF tissue samples from large organs in all patients with meningococcal septic shock. The lungs are the organs with the highest LPS and Nm DNA concentration followed by the heart in two of the three meningococcal shock patients. Nm DNA was not detected in any plasma or tissue sample from patients with lethal pneumococcal infection. LPS was detected at a low level in all FF tissues from the two patients with lethal pneumococcal disease. The experimental porcine meningococcal septic shock model indicates that also in porcinis the highest LPS and Nm DNA concentration are detected in lungs tissue samples. The quantification analysis showed that the highest concentration of both Nm DNA and LPS are in the organs and not in the circulation of patients with lethal meningococcal septic shock. This was also shown in the experimental porcine meningococcal septic shock model.ConclusionOur results suggest that LPS can be quantified in mammalian tissues by using the LAL assay.

Project description:OBJECTIVES:Cell death in lymphatic organs, such as the spleen, is in part responsible for immunosuppression and contributes to mortality during sepsis. An early and noninvasive detection of lymphoid cell death could thus have significant clinical implications. Here, we tested in vivo imaging of lymphoid cell death using a near-infrared annexin V (AV-750). DESIGN:Animal study. SETTING:Laboratory investigation. SUBJECTS:C57BL/6J wild-type and toll-like receptor 3 knockout mice. INTERVENTIONS:Mild and severe polymicrobial sepsis was induced with cecum ligation and puncture. Serum cytokines and acute kidney injury markers were tested by immunoassay and quantitative reverse transcription-polymerase chain reaction, respectively. Sepsis-induced lymphoid cell death was detected by fluorescent AV-750 accumulation in the thorax and abdomen (in vivo), in isolated organs (ex vivo), and in isolated cells (flow cytometry). Caspase-3 cleavage/activity and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining were tested for apoptosis. MEASUREMENTS AND MAIN RESULTS:Severe sepsis induced marked apoptosis in the thymus, spleen, and liver as demonstrated by cleaved caspase-3 and an increase in caspase-3 activity and terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. A significant increase in fluorescent AV-750 signal was seen in the thoracic and upper abdominal fields and associated with the severity of sepsis. The in vivo thoracic and abdominal AV-750 fluorescent signal was attributed to the thymus, liver, and spleen as determined by ex vivo imaging and highly correlated with the levels of cell death in thymocytes and splenocytes, respectively, as measured by flow cytometry. Compared with wild-type septic mice, toll-like receptor 3 septic mice had attenuated abdominal AV-750 fluorescent signal, reduced ex vivo fluorescence in the spleen, and decreased splenocyte cell death. CONCLUSIONS:In vivo AV-750 fluorescent imaging provides spatially resolved and organ-specific detection of lymphoid cell death during polymicrobial sepsis. The AV-750 fluorescent intensity in the thoracic and abdominal fields is associated with sepsis severity and well correlated with sepsis-induced cell death in the thymus and spleen, respectively.

Project description:BackgroundThe gut microbiome plays a protective role in the host defense against pneumonia. The composition of the lung microbiota has been shown to be predictive of clinical outcome in critically ill patients. However, the dynamics of the lung and gut microbiota composition over time during severe pneumonia remains ill defined. We used a mouse model of pneumonia-derived sepsis caused by Klebsiella pneumoniae in order to follow the pathogen burden as well as the composition of the lung, tongue and fecal microbiota from local infection towards systemic spread.ResultsAlready at 6 h post-inoculation with K. pneumoniae, marked changes in the lung microbiota were seen. The alpha diversity of the lung microbiota did not change throughout the infection, whereas the beta diversity did. A shift between the prominent lung microbiota members of Streptococcus and Klebsiella was seen from 12 h onwards and was most pronounced at 18 h post-inoculation (PI) which was also reflected in the release of pro-inflammatory cytokines indicating severe pulmonary inflammation. Around 18 h PI, K. pneumoniae bacteremia was observed together with a systemic inflammatory response. The composition of the tongue microbiota was not affected during infection, even at 18-30 h PI when K. pneumoniae had become the dominant bacterium in the lung. Moreover, we observed differences in the gut microbiota during pulmonary infection. The gut microbiota contributed to the lung microbiota at 12 h PI, however, this decreased at a later stage of the infection.ConclusionsAt 18 h PI, K. pneumoniae was the dominant member in the lung microbiota. The lung microbiota profiles were significantly explained by the lung K. pneumoniae bacterial counts and Klebsiella and Streptococcus were correlating with the measured cytokine levels in the lung and/or blood. The oral microbiota in mice, however, was not influenced by the severity of murine pneumonia, whereas the gut microbiota was affected. This study is of significance for future studies investigating the role of the lung microbiota during pneumonia and sepsis.

Dataset Information

Imaging of disease dynamics during meningococcal sepsis.

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Imaging of disease dynamics during meningococcal sepsis.

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