Osteopontin Impairs Host Defense during Established Gram-Negative Sepsis Caused by Burkholderia pseudomallei (Melioidosis)

Melioidosis is a severe tropical disease caused by infection with the bacterium Burkholderia (B.) pseudomallei. In northeast Thailand infection with this bacterium is the major cause of community-acquired septicemia with a mortality rate up to 40%. Extending the knowledge on the mechanisms of host defense against B. pseudomallei infection would be helpful to improve treatment of this severe illness. Osteopontin (OPN) is a cytokine that is involved in several immune responses that occur during bacterial infection. In this study, we investigated levels of OPN in patients with melioidosis, and studied the function of OPN during experimental melioidosis in mice. We found that OPN concentrations were elevated in patients with severe melioidosis, and that high OPN concentrations are associated with poor outcome in patients with melioidosis. In experimental melioidosis in mice plasma and lung OPN levels were also increased. Moreover, mice with melioidosis that were deficient for OPN demonstrated reduced bacterial numbers in their lungs, diminished pulmonary tissue injury, and decreased neutrophil infiltration into the lungs during established melioidosis. Moreover, these mice displayed a delayed mortality as compared to control mice. In conclusion, sustained production of OPN impairs host defense during melioidosis

Expression and Function of Macrophage Migration Inhibitory Factor (MIF) in Melioidosis

Melioidosis is a severe tropical infection caused by the bacterium Burkholderia pseudomallei. B. pseudomallei is the major cause of community-acquired septicemia in northeast Thailand with a mortality rate in severe cases of around 40% Little is known, however, about the mechanisms of the host defense to B. pseudomallei infection. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that has emerged as an important mediator of the host defense in severe bacterial infections. In this article, we studied the expression and function of MIF both in patients with melioidosis and in mice during experimental melioidosis. We found that MIF concentrations were elevated in patients with melioidosis. Furthermore, high MIF concentrations are associated with poor outcome in patients with melioidosis. Also, in mice with experimentally induced melioidosis, we observed an upregulation of MIF concentrations. Furthermore, mice with melioidosis that were treated with a MIF blocking treatment showed lower bacterial counts in their lungs during infection. In conclusion, MIF seems to impair host defense mechanisms during melioidosis

The Urokinase Receptor (uPAR) Facilitates Clearance of Borrelia burgdorferi

The causative agent of Lyme borreliosis, the spirochete Borrelia burgdorferi, has been shown to induce expression of the urokinase receptor (uPAR); however, the role of uPAR in the immune response against Borrelia has never been investigated. uPAR not only acts as a proteinase receptor, but can also, dependently or independently of ligation to uPA, directly affect leukocyte function. We here demonstrate that uPAR is upregulated on murine and human leukocytes upon exposure to B. burgdorferi both in vitro as well as in vivo. Notably, B. burgdorferi-inoculated C57BL/6 uPAR knock-out mice harbored significantly higher Borrelia numbers compared to WT controls. This was associated with impaired phagocytotic capacity of B. burgdorferi by uPAR knock-out leukocytes in vitro. B. burgdorferi numbers in vivo, and phagocytotic capacity in vitro, were unaltered in uPA, tPA (low fibrinolytic activity) and PAI-1 (high fibrinolytic activity) knock-out mice compared to WT controls. Strikingly, in uPAR knock-out mice partially backcrossed to a B. burgdorferi susceptible C3H/HeN background, higher B. burgdorferi numbers were associated with more severe carditis and increased local TLR2 and IL-1β mRNA expression. In conclusion, in B. burgdorferi infection, uPAR is required for phagocytosis and adequate eradication of the spirochete from the heart by a mechanism that is independent of binding of uPAR to uPA or its role in the fibrinolytic system

Fatty Acid Oxidation in Macrophages and T Cells: Time for Reassessment?

Previous immunometabolism research using the CPT1 inhibitor etomoxir suggests that long-chain fatty acid oxidation (LC-FAO) supports IL-4-driven alternative macrophage activation (M(IL-4)) and regulates memory and regulatory T cell formation. Divakaruni et al. (2018) and Raud et al. (2018) now report that LC-FAO is largely dispensable for these processes

CD14 contributes to pulmonary inflammation and mortality during murine tuberculosis

Toll-like receptors play an essential role in the innate recognition of micro-organisms by the host. CD14 is one of the extracellular adaptor proteins required for recognition of Gram-negative bacteria and possibly also Mycobacterium tuberculosis. Therefore, we intranasally infected wild-type (WT) and CD14 knock-out (KO) mice with virulent M. tuberculosis H37Rv. We found no differences in bacterial load in the main target organ lung up to 32 weeks after infection. From 20 weeks onward 57% of WT mice succumbed, whereas all CD14 KO mice survived. The improved outcome of CD14 KO mice was accompanied by reduced pulmonary inflammation; lung cell counts and percentage of inflamed lung tissue were reduced in CD14 WT mice. These data suggest that during chronic infection CD14 KO mice are protected from lethality caused by lung tuberculosis because of a reduction of the inflammatory respons

CD44 Deficiency Is Associated with Enhanced Escherichia coli-Induced Proinflammatory Cytokine and Chemokine Release by Peritoneal Macrophages ▿

CD44 is involved in several immune responses, such as cellular adhesion, migration, proliferation, and activation. Peritonitis is an important cause of sepsis, and Escherichia coli is one of the major pathogens involved therein. We sought to determine the role of CD44 in the host response to E. coli-induced abdominal sepsis and to assess the function of CD44 in the activation of primary peritoneal macrophages by E. coli or lipopolysaccharide (LPS) purified from this bacterium by using wild-type (WT) and CD44 knockout (KO) mice. CD44 KO mice already demonstrated enhanced CXC chemokine levels in peritoneal lavage fluid at 6 h after infection, whereas tumor necrosis factor alpha (TNF-α) and interleukin-6 levels were elevated at 20 h postinfection. In line with this, CD44 KO mouse peritoneal macrophages released more TNF-α and macrophage inflammatory protein 2 (MIP-2) than did WT cells upon stimulation with E. coli or LPS in the presence of autologous serum. In contrast, plasma TNF-α levels were lower in CD44 KO mice and CD44 KO blood leukocytes secreted similar amounts of TNF-α and MIP-2 upon ex vivo incubation with E. coli or LPS. The proinflammatory phenotype of CD44 KO macrophages was not associated with an altered expression of inhibitors of Toll-like receptor signaling, whereas it could be partially reversed by addition of WT serum. CD44 deficiency did not impact on leukocyte recruitment into the peritoneal cavity or organ failure. These data suggest that CD44 differentially influences cytokine and chemokine release by different leukocyte subsets

Osteopontin is not crucial to protective immunity during murine tuberculosis

Upon infection with Mycobacterium (M.) tuberculosis, the development of a strong T helper 1 (Th1)-mediated adaptive immune response is considered as being most important for containment of the infection. Osteopontin (OPN) is a phosphorylated glycoprotein that is chemotactic for inflammatory cells and has been implicated in the induction of Th1 responses and granulomatous disease. We tested the hypothesis that OPN facilitates protective immunity during M. tuberculosis infection using wild-type (WT) and OPN knockout (KO) mice in a model of pulmonary tuberculosis. OPN expression was up-regulated in alveolar macrophages and lymphoid cells during M. tuberculosis infection. There were no significant differences in bacterial outgrowth, inflammation or recruitment of lymphocytes, macrophages and polymorphonuclear cells in the lungs after 2 and 5 weeks of infection. However, the numbers of CD4(+) and CD8(+) T cells were reduced in the absence of OPN 5 weeks after infection. Similar concentrations of cytokine were observed in lungs from both WT mice and OPN KO mice; however, there was a trend towards decreased levels of interferon-gamma (IFN-gamma) in OPN KO mice 5 weeks after infection. Despite an unaltered immune response in the early phase of tuberculosis, OPN KO mice had a modest survival advantage. Of note, both pulmonary bacterial loads and lung inflammation were reduced in these mice 31 weeks after infection. These data suggest that OPN is not crucial for protective immunity upon M. tuberculosis infection and during the late phase of tuberculosis may even be detrimental for the hos

CD44 Is Protective during Hyperoxia-Induced Lung Injury

Patients with acute lung injury or respiratory distress syndrome often require supplemental oxygen to maintain tissue oxygenation; however, this treatment can cause or worsen lung inflammation. CD44 is a transmembrane adhesion molecule that is present on a wide variety of cell types, including leukocytes and parenchymal cells, and is an important player in leukocyte trafficking. The aim of this study was to determine the role of CD44 during hyperoxia-induced (> 95% oxygen) acute lung injury. Whereas all wild-type mice survived the 72-hour observation period, 37.5% of CD44 knockout (KO) mice died. CD44 deficiency was associated with a profound influx of neutrophils into the bronchoalveolar space, in the presence of similar or even lower neutrophil numbers in lung parenchyma, suggesting that CD44 is important for containing neutrophils in the pulmonary interstitium during hyperoxia. In addition, CD44 deficiency resulted in increased IL-6 and keratinocyte-derived chemokine release into bronchoalveolar lavage fluid (BALF). CD44 KO mice further displayed evidence for increased vascular leak and injury of type II respiratory epithelial cells. CD44 protected against bronchial epithelial cell death, as shown by increased epithelial cell necrosis and a trend toward increased BALF nucleosome levels in CD44 KO mice. CD44 can bind and internalize hyaluronic acid (HA), which acts proinflammatory. Concentrations of HA increased in BALF from CD44 KO but not wild-type mice during hyperoxia. These data suggest that CD44 protects against hyperoxia-induced lung injury and mortality by a mechanism that at least in part relies on its ability to clear HA from the bronchoalveolar spac

ST2 deficient mice display a normal host defense against pulmonary infection with Mycobacterium tuberculosis

Tuberculosis, caused by Mycobacterium (M.) tuberculosis, is a devastating infectious disease causing many deaths world-wide every year. Successful host defense mainly depends on a strong Th type I response. We investigated the role of T1/ST2 (recently identified as the receptor for IL-33), a typical Th2 marker in the assumption that a shift towards a beneficial Th I response would Occur in the absence of ST2. For this, ST2 KO and WT mice were intranasally infected with a virulent strain of M. tuberculosis (150 CFU). In line with our hypothesis, ST2 KO animals displayed increased numbers of lymphocytes infiltrating the lung after 2 weeks of infection, increased IFN gamma production by splenocytes in ST2 KO mice early in infection and enhanced lung IFN gamma levels at the chronic phase of the disease. However, we did not detect any differences between ST2 KO and WT mice in mycobacterial loads in lungs or liver after M. tuberculosis infection. The pulmonary inflammatory response, as measured by relative lung weights, cytokine and chemokine levels as well as histopathological analysis, was similar in ST2 KO and WT mice. These data suggest that apart from inducing a modest shift towards the Th I response, the role of ST2 during murine M. tuberculosis infection is limited. (C) 2009 Elsevier Masson SAS. All rights reserve