Immune status in sepsis: the bug, the site of infection and the severity can make the difference

Studying a large number of patients with sepsis, the Hellenic sepsis study group led by Evangello Giamarellos-Bourboulis emphasizes that the nature of the bacterial infection, its origin (community or nosocomial), its site, and its severity exert different pressures on the immune system. Their study illustrates the heterogeneity of patients with sepsis and points out that numerous key parameters of severe infection influence immune status

In vivo bioluminescence imaging and histopathopathologic analysis reveal distinct roles for resident and recruited immune effector cells in defense against invasive aspergillosis

BACKGROUND: Invasive aspergillosis (IA) is a major cause of infectious morbidity and mortality in immune compromised patients. Studies on the pathogenesis of IA have been limited by the difficulty to monitor disease progression in real-time. For real-time monitoring of the infection, we recently engineered a bioluminescent A. fumigatus strain. RESULTS: In this study, we demonstrate that bioluminescence imaging can track the progression of IA at different anatomic locations in a murine model of disease that recapitulates the natural route of infection. To define the temporal and functional requirements of distinct innate immune cellular subsets in host defense against respiratory A. fumigatus infection, we examined the development and progression of IA using bioluminescence imaging and histopathologic analysis in mice with four different types of pharmacologic or numeric defects in innate immune function that target resident and recruited phagocyte subsets. While bioluminescence imaging can track the progression and location of invasive disease in vivo, signals can be attenuated by severe inflammation and associated tissue hypoxia. However, especially under non-inflammatory conditions, such as cyclophosphamide treatment, an increasing bioluminescence signal reflects the increasing biomass of alive fungal cells. CONCLUSIONS: Imaging studies allowed an in vivo correlation between the onset, peak, and kinetics of hyphal tissue invasion from the lung under conditions of functional or numeric inactivation of phagocytes and sheds light on the germination speed of conidia under the different immunosuppression regimens. Conditions of high inflammation -either mediated by neutrophil influx under corticosteroid treatment or by monocytes recruited during antibody-mediated depletion of neutrophils- were associated with rapid conidial germination and caused an early rise in bioluminescence post-infection. In contrast, 80% alveolar macrophage depletion failed to trigger a bioluminescent signal, consistent with the notion that neutrophil recruitment is essential for early host defense, while alveolar macrophage depletion can be functionally compensated

Interferon-gamma and granulocyte/monocyte colony-stimulating factor production by natural killer cells involves different signaling pathways and the adaptor stimulator of interferon genes (STING)

Natural killer (NK) cells are important for innate immunity in particular through the production of IFN-gamma and GM-CSF. Both cytokines are important in restoration of immune function of tolerized leukocytes under inflammatory events. The expression of TLRs in NK cells has been widely studied by analyzing the mRNA of these receptors, rarely seeking their protein expression. We previously showed that murine spleen NK cells express TLR9 intracellularly and respond to CpG oligodeoxynucleotide (CpG-ODN) by producing IFN-gamma and GM-CSF. However, to get such production the presence of accessory cytokines (such as IL-15 and IL-18) was required, whereas CpG-ODN or accessory cytokines alone did not induce IFN-gamma or GM-CSF. We show here that TLR9 overlaps with the Golgi apparatus in NK cells. Furthermore, CpG-ODN stimulation in the presence of accessory cytokines induces the phosphorylation of c-Jun, STAT3, and IkappaBalpha. IFN-gamma and GM-CSF production requires NF-kappaB and STAT3 activation as well as Erk-dependent mechanisms for IFN-gamma and p38 signaling for GM-CSF. Using knock-out-mice, we show that UNC93b1 and IL-12 (produced by NK cells themselves) are also necessary for IFN-gamma and GM-CSF production. IFN-gamma production was found to be MyD88- and TLR9-dependent, whereas GM-CSF was TLR9-independent but dependent on STING (stimulator of interferon genes), a cytosolic adaptor recently described for DNA sensing. Our study thereby allows us to gain insight into the mechanisms of synergy between accessory cytokines and CpG-ODN in NK cells. It also identifies a new and alternative signaling pathway for CpG-ODN in murine NK cells

High-mobility group box 1 as a surrogate prognostic marker in dogs with systemic inflammatory response syndrome

To evaluate various surrogate markers associated with the inflammatory and counter-inflammatory responses with respect to mortality in dogs with systemic inflammatory response syndrome (SIRS).Prospective observational study.Veterinary Teaching Hospital.Twenty-eight dogs with naturally occurring diseases and SIRS from January 2007 to May 2009.Upon admission to the veterinary hospital, history and baseline data from the physical examination, including parameters previously defined for meeting SIRS criteria, were documented. Heparinized blood samples were collected and plasma cytokines interleukin-6 (IL-6), IL-10, and high-mobility group box 1 (HMGB1) were measured by sandwich ELISA.In nonsurvivors, median plasma HMGB1 concentrations (0.718 μg/L, interquartile range [IQR]; 0.300–1.626 μg/L) and the ratio of HMGB1 to IL-10 (2.236, IQR; 0.972–5.367) were significantly increased as compared with those found in survivors (0.300 μg/L, IQR; 0.300–0.312 μg/L for HMGB1; 1.017, IQR; 0.862–1.126 for the ratio of HMGB1 to IL-10, P =0.007 and 0.024, respectively). Plasma IL-6, IL-10, and the ratio of IL-6 to IL-10 were not significantly different between groups. Among the parameters studied, HMGB1 and the ratio of HMGB1 to IL-10 performed the best in discriminating outcome in dogs with SIRS according to receiver operator characteristic curve analysis.Increases in plasma HMGB1 concentration and the ratio of HMGB1 to IL-10 may predict poorer outcomes in dogs with SIRS. The approach described may lead to reliable prognostic biomarkers and new therapeutic concepts in the study of SIRS in dogs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79125/1/j.1476-4431.2010.00539.x.pd

Acute-phase reactants after paediatric cardiac arrest. Procalcitonin as marker of immediate outcome

<p>Abstract</p> <p>Objective</p> <p>Procalcitonin (PCT) and C reactive protein (CRP) have been used as infection parameters. PCT increase correlates with the infection's severity, course, and mortality. Post-cardiocirculatory arrest syndrome may be related to an early systemic inflammatory response, and may possibly be associated with an endotoxin tolerance. Our objective was to report the time profile of PCT and CRP levels after paediatric cardiac arrest and to assess if they could be use as markers of immediate survival.</p> <p>Materials and methods</p> <p>A retrospective observational study set in an eight-bed PICU of a university hospital was performed during a period of two years. Eleven children younger than 14 years were admitted in the PICU after a cardiac arrest. PCT and CRP plasma concentrations were measured within the first 12 and 24 hours of admission.</p> <p>Results</p> <p>In survivors, PCT values increased 12 hours after cardiac arrest without further increase between 12 and 24 hours. In non survivors, PCT values increased 12 hours after cardiac arrest with further increase between 12 and 24 hours. Median PCT values (range) at 24 hours after cardiac arrest were 22.7 ng/mL (0.2 – 41.0) in survivors vs. 205.5 ng/mL (116.6 – 600.0) in non survivors (p < 0.05). CRP levels were elevated in all patients, survivors and non-survivors, at 12 and 24 hours without differences between both groups.</p> <p>Conclusion</p> <p>Measurement of PCT during the first 24 hours after paediatric cardiac arrest could serve as marker of mortality.</p

CpG-ODN and MPLA Prevent Mortality in a Murine Model of Post-Hemorrhage-Staphyloccocus aureus Pneumonia

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-α), Interferon-beta (IFN-β) 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-α, IFN-β and IL-12p40) and decreased mortality of post-hemorrhage MSSA pneumonia