Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004623 (bacterial infection)
 15,226 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Idiopathic purpura fulminans usually occurs in young children and is frequently preceded by a preparatory viral or bacterial infection. Following a severe streptococcal pharyngitis, an 8-year-old boy developed purpura fulminans with disseminated intravascular coagulation and severe protein S deficiency (total antigen < 0.05 u/ml). Despite generous plasma infusions, skin necrosis progressed rapidly into compartment syndrome which required fasciotomy and skin grafting and resulted in the loss of three digits of the right foot. Total protein S remained low for over a month despite plasma supplementation and complete normalization of protein C levels. A polyclonal anti-protein S IgG was demonstrated in the patient's plasma, which decreased to 25% of baseline titre after 1 month and was undetectable 6 months after purpura fulminans, when plasma protein S had returned to normal. Transient, isolated and severe deficiencies of protein S have been reported in patients with idiopathic purpura fulminans and a previous preparatory infection. Autoimmune protein S deficiency may play a key role in the aetiopathogenesis of idiopathic purpura fulminans.
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PMID:Severe autoimmune protein S deficiency in a boy with idiopathic purpura fulminans. 773 61

Cells of the macrophage lineage are required to cope with bacterial infection and to serve as APC for T lymphocytes. Among the regulatory factors limiting the macrophage response to infection and the expansion of Ag-specific T cells, IL-10 has received recent attention. On monocytes/macrophages, IL-10 has been shown to inhibit the intracellular killing of bacteria, the secretion of cytokines, and the expression of MHC molecules. In the present study we have examined the effect of IL-10 on different APC obtained from the central nervous system. Both, astrocytes and microglial cells are in a resting state and require activation signals to express MHC class II and cytokine genes. Whereas IL-10 profoundly inhibits the IFN-gamma-induced expression of MHC class II Ag on microglial cells, it had no such effects on astrocytes. Nevertheless, IL-10 suppressed the MHC class II- and Ag-dependent proliferative response of T cells in the presence of both types of APC. As shown by the use of anti-IL-10 Abs, endogenously produced IL-10 influenced the function of microglia but not of astrocytes to serve as APC. IL-10 significantly inhibited the LPS-induced production of granulocyte-macrophage-CSF, macrophage-CSF, and IL-6 by both astrocytes and microglial cells. In contrast, the secretion of these cytokines by the two glial cell population was not altered by IL-10 when IL-1 beta, TNF-alpha, or viruses were used as stimuli.
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PMID:Antigen presentation in the central nervous system. The inhibitory effect of IL-10 on MHC class II expression and production of cytokines depends on the inducing signals and the type of cell analyzed. 814 79

Inflammation often is considered a contributing factor to both thrombosis and disseminated intravascular coagulation. The molecular mechanisms that dictate which of these clinical manifestations will result from the inflammatory stimulus remain obscure. Bacterial infection and certain tumors are common initiators of the disseminated intravascular coagulant response. Complement activation resulting from bacterial infection shares with selected tumors the capacity to generate or release membrane particles that lack functional adhesion receptors and hence could circulate to amplify a disseminated intravascular coagulant response. We developed a model of venous thrombosis that resulted in localized thrombus formation without disseminated intravascular coagulation. The model involves infusion of tumor necrosis factor, blockade of protein C and a partial decrease in venous flow caused by ligation of the superficial femoral vein without obstruction of the deep formal vein. Infusion of phospholipid vesicles into this model resulted in amplification of a localized thrombotic response into a consumptive response. Seven different groups of animals were studied. The first three groups established the conditions necessary to produce deep vein thrombosis. The second four groups established the conditions necessary to produce disseminated intravascular coagulation. The infusion of phospholipid vesicles plus tumor necrosis factor and anti-protein C antibody resulted in consumption of fibrinogen, the production of thrombin/antithrombin complexes, a fall in platelet count, and venous thrombosis. Without ligation and catheterization phospholipid vesicles failed to produce the consumptive response. We conclude, therefore, that phospholipid vesicles can amplify a local thrombotic response into a consumptive response, and that vesiculation accompanying inflammation is one means by which localized coagulant activity may be amplified to produce disseminated intravascular coagulation.
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PMID:Infusion of phospholipid vesicles amplifies the local thrombotic response to TNF and anti-protein C into a consumptive response. 874 82

Sepsis-induced abnormalities of coagulation may contribute to mortality during severe bacterial infection. The aim of this study was to examine changes in coagulation parameters and to assess the role of protein C supplementation during murine S. aureus sepsis. Gram-positive sepsis was characterized by a hypercoagulable state with predominant activation of the external coagulation pathway, registered as an early increase of tissue factor activity and concomitant reduction in protein C. The internal coagulation pathway was unaffected. No correlation between the changes of coagulation parameters and the intensity of inflammation, determined as serum IL-6 levels, was found. Supplementation with neither protein C or APC favoured survival in S. aureus sepsis. Reduction in thrombin generation in response to protein C supplementation was associated with significantly increased survival.
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PMID:Thrombin generation and mortality during Staphylococcus aureus sepsis. 1131 18

In vivo priming of CD8(+) T lymphocytes against exogenously processed model Ags requires CD4(+) T cell help, specifically interactions between CD40 ligand (CD40L) expressed by activated CD4(+) T cells and CD40, which is present on professional APC such as dendritic cells (DCs). To address this issue in the context of bacterial infection, we examined CD40L-CD40 interactions in CD8(+) T cell priming against an exogenously processed, nonsecreted bacterial Ag. CD40L interactions were blocked by in vivo treatment with anti-CD40L mAb MR-1, which inhibited germinal center formation and CD8(+) T cell cross-priming against an exogenous model Ag, OVA. In contrast, MR-1 treatment did not interfere with CD8(+) T cell priming against a nonsecreted or secreted recombinant Ag expressed by Listeria monocytogenes. Memory and secondary responses of CD8(+) T cells against nonsecreted and secreted bacterial Ags were also largely unimpaired by transient MR-1 treatment. When MR-1-treated mice were concurrently immunized with L. monocytogenes and OVA-loaded splenocytes, cross-priming of OVA-specific naive CD8(+) T cells occurred. No significant decline in cross-priming against OVA was measured when either TNF or IFN-gamma was neutralized in L. monocytogenes-infected animals, demonstrating that multiple signals exist to overcome CD40L blockade of CD8(+) T cell cross-priming during bacterial infection. These data support a model in which DCs can be stimulated in vivo through signals other than CD40, becoming APC that can effectively stimulate CD8(+) T cell responses against exogenous Ags during infection.
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PMID:Listeria monocytogenes infection overcomes the requirement for CD40 ligand in exogenous antigen presentation to CD8(+) T cells. 1169 31

In the present study, we investigated in vivo the infection and APC functions of dendritic cells (DC) and macrophages (Mphi) after administration of live mycobacteria to mice. Experiments were conducted with Mycobacterium bovis bacillus Calmette-Guerin (BCG) or a rBCG expressing a reporter Ag. Following infection of mice, DC and Mphi were purified and the presence of immunogenic peptide/MHC class II complexes was detected ex vivo on sorted cells, as was the secretion of IL-12 p40. We show in this study that DC is a host cell for mycobacteria, and we provide an in vivo detailed picture of the role of Mphi and DC in the mobilization of immunity during the early stages of a bacterial infection. Strikingly, BCG bacilli survive but remain stable in number in the DC leukocyte subset during the first 2 wk of infection. As Ag presentation by DC is rapidly lost, this suggests that DC may represent a hidden reservoir for mycobacteria.
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PMID:Dendritic cells are host cells for mycobacteria in vivo that trigger innate and acquired immunity. 1180 68

CD4 T cells are known to assist the CD8 T cell response by activating APC via CD40-CD40 ligand (L) interactions. However, recent data have shown that bacterial products can directly activate APC through Toll-like receptors, resulting in up-regulation of costimulatory molecules necessary for the efficient priming of naive T cells. It remains unclear what role CD4 T cell help and various costimulation pathways play in the development of CD8 T cell responses during bacterial infection. In this study, we examined these questions using an intracellular bacterium, Listeria monocytogenes, as a model of infection. In CD4 T cell-depleted, CD4(-/-), and MHC class II(-/-) mice, L. monocytogenes infection induced CD8 T cell activation and primed epitope-specific CD8 T cells to levels commensurate with those in normal C57BL/6 mice. Furthermore, these epitope-specific CD8 T cells established long-term memory in CD4(-/-) mice that was capable of mounting a protective recall response. In vitro analysis showed that L. monocytogenes directly stimulated the activation and maturation of murine dendritic cells. The CD8 T cell response to L. monocytogenes was normal in CD40L(-/-) mice but defective in CD28(-/-) and CD137L(-/-) mice. These data show that in situations where infectious agents or immunogens can directly activate APC, CD8 T cell responses are less dependent on CD4 T cell help via the CD40-CD40L pathway but involve costimulation through CD137-CD137L and B7-CD28 interactions.
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PMID:Role of CD4 T cell help and costimulation in CD8 T cell responses during Listeria monocytogenes infection. 1257 76

We investigated the effect of an i.v. infusion of highly purified vitamin B(2) (riboflavin 5'-sodium phosphate: purity >97%) on lipopolysaccharide-induced shock and bacterial infection in mice. Six hours after lipopolysaccharide injection or 1 h after bacterial infection, vitamin B(2) or human activated protein C (APC) was administered by 6-h i.v. infusion. Vitamin B(2) at 10 mg/kg/6 h and up to 80 mg/kg/6 h significantly improved lipopolysaccharide-induced endotoxin shock. APC was also effective at low doses, but was deleterious at higher doses. Moreover, vitamin B(2) at 80 mg/kg/6 h significantly reduced the lethality of Escherichia coli and Staphylococcus aureus infection, whereas APC at up to 600 units/kg/6 h was ineffective. The i.v. infusion of vitamin B(2) reduced the elevations of proinflammatory cytokines and nitric oxide induced by lipopolysaccharide. These results suggest that i.v. infusion of vitamin B(2) represents a promising strategy for the treatment of sepsis and septic shock.
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PMID:Effects of intravenous infusion of highly purified vitamin B2 on lipopolysaccharide-induced shock and bacterial infection in mice. 1517 75

Overwhelming gram-negative bacterial infection and life-threatening systemic inflammation are widespread problems in critically ill emergency department patients. Currently, the treatment of these patients is largely supportive, focusing on antibiotics, fluids, hemodynamic and ventilatory support, and intensive monitoring. The only Food and Drug Administration-approved pharmaceutical agent for the treatment of sepsis is activated protein C, with its use largely relegated to the intensive care unit. The subject thus remains an active area of exploration for emergency medicine research. During sepsis and inflammation, innate immune cells release excessive amounts of proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1beta. If delivered early enough, anti-TNF antibodies can be an effective therapy in experimental models of septic shock. Anti-TNF antibodies have been developed for clinical use in rheumatoid arthritis and Crohn's disease. However, anti-TNF treatment for sepsis has been difficult to achieve in the clinical setting, perhaps because TNF's early release and transient appearance in the serum create a narrow therapeutic window. An alternative strategy would be to identify "late" mediators that may be clinically more accessible. High mobility group box 1 (HMGB1), a protein previously known only as a nuclear transcription factor, is now implicated as a late mediator of sepsis. Targeting late mediators of lethal systemic inflammation represents a novel approach that may widen the therapeutic window and lead to new strategies for inhibiting the deleterious effects of the inflammatory cascade. Here the authors review the studies that led to the discovery of HMGB1 as a late mediator of systemic inflammation and discuss the possibility of HMGB1 as a therapeutic target for septic patients in the emergency department.
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PMID:Bench to bedside: HMGB1-a novel proinflammatory cytokine and potential therapeutic target for septic patients in the emergency department. 1528 94

Transmembrane signaling adaptor DAP12 has increasingly been recognized for its important role in innate responses. However, its role in the regulation of antimicrobial T cell responses has remained unknown. In our current study, we have examined host defense, T cell responses, and tissue immunopathology in models of intracellular infection established in wild-type and DAP12-deficient mice. During mycobacterial infection, lack of DAP12 leads to pronounced proinflammatory and Th1 cytokine responses, overactivation of Ag-specific CD4 and CD8 T cells of type 1 phenotype, and heightened immunopathology both in the lung and lymphoid organs. DAP12-deficient airway APC display enhanced NF-kappaB activation and cytokine responses upon TLR stimulation or mycobacterial infection in vitro. Of importance, adoptive transfer of Ag-loaded DAP12-deficient APC alone could lead to overactivation of transferred transgenic or endogenous wild-type T cells in vivo. We have further found that the immune regulatory role by DAP12 is not restricted only to intracellular bacterial infection, since lack of this molecule also leads to uncontrolled type 1 T cell activation and severe immunopathology and tissue injury during intracellular viral infection. Our study thus identifies DAP12 as an important novel immune regulatory molecule that acts, via APC, to control the level of antimicrobial type 1 T cell activation and immunopathology.
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PMID:Critical negative regulation of type 1 T cell immunity and immunopathology by signaling adaptor DAP12 during intracellular infection. 1778 40


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