A phosphatidylserine-binding site in the cytosolic fragment of Clostridium sordellii lethal toxin facilitates glucosylation of membrane-bound Rac and is required for cytotoxicity.
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Large clostridial toxins glucosylate some small G proteins on a threonine residue, thereby preventing their interactions with effector molecules and regulators. We show that the glucosyltransferase domain of lethal toxin from Clostridium sordellii (LT(cyt); amino acids 1-546), which is released into the cytosol during cell infection, binds preferentially to liposomes containing phosphatidylserine as compared with other anionic lipids. The binding of LT(cyt) to phosphatidylserine increases by two orders of magnitude the rate of glucosylation of liposome-bound geranyl-geranylated Rac-GDP. Limited proteolysis and deletion studies show that the binding site for phosphatidylserine lies within the first 18 N-terminal residues of LT(cyt). Deletion of these residues abolishes the effect of phosphatidylserine on the activity of LT(cyt) on liposome-bound geranyl-geranylated Rac-GDP and prevents the morphological effects induced by LT(cyt) microinjection into various cells, but it does not affect the intrinsic activity of LT(cyt) on non-geranyl-geranylated Rac-GDP in solution. We conclude that the avidity of LT(cyt) for phosphatidylserine facilitates its targeting to the cytosolic leaflet of cell membranes and, notably, the plasma membrane, where this anionic lipid is abundant and where several targets of lethal toxin reside. (+info)
Clostridium sordellii toxic shock syndrome after medical abortion with mifepristone and intravaginal misoprostol--United States and Canada, 2001-2005.
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On July 19, 2005, the Food and Drug Administration (FDA) issued a public health advisory regarding the deaths of four women in the United States after medical abortions with Mifeprex (mifepristone, formerly RU-486; Danco Laboratories, New York, New York) and intravaginal misoprostol. Two of these deaths occurred in 2003, one in 2004, and one in 2005. Two of these U.S. cases had clinical illness consistent with toxic shock and had evidence of endometrial infection with Clostridium sordellii, a gram-positive, toxin-forming anaerobic bacteria. In addition, a fatal case of C. sordellii toxic shock syndrome after medical abortion with mifepristone and misoprostol was reported in 2001, in Canada. All three cases of C. sordellii infection were notable for lack of fever, and all had refractory hypotension, multiple effusions, hemoconcentration, and a profound leukocytosis. C. sordellii previously has been described as a cause of pregnancy-associated toxic shock syndrome. (+info)
Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion.
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Endometritis and toxic shock syndrome associated with Clostridium sordellii have previously been reported after childbirth and, in one case, after medical abortion. We describe four deaths due to endometritis and toxic shock syndrome associated with C. sordellii that occurred within one week after medically induced abortions. Clinical findings included tachycardia, hypotension, edema, hemoconcentration, profound leukocytosis, and absence of fever. These cases indicate the need for physician awareness of this syndrome and for further study of its association with medical abortion. (+info)
Sudden death associated with Clostridium sordellii in captive lions (Panthera leo).
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In the spring of 2003, a series of sudden deaths in a group of adult lions (Panthera leo) with a previous history of depression, inanition, and lethargy, was investigated. Five animals died within 24 to 36 hours after onset of signs of disease. Serologic screening for viral disease detection was negative, evidence of parasites was not detected, and results of a complete blood count and serum biochemical analysis were within reference intervals in all lions. The most relevant lesions observed were multiple areas of necrosis and hemorrhage in the intestinal outer muscular layer, and cellulitis with an intense bloody edema in the mesenteric and the pericardial fat tissue. On the basis of the fulminant course of the disease, the gross and histologic findings, and the isolation and identification of Clostridium sordellii, a diagnosis of infectious myositis and cellulitis associated with acute clostridiosis was made. To the authors' knowledge, this is the first report of sudden death associated with C. sordellii in felines. (+info)
Clostridium sordellii infection: epidemiology, clinical findings, and current perspectives on diagnosis and treatment.
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Clostridium sordellii infections pose difficult clinical challenges and are usually fatal. Most commonly, these infections occur after trauma, childbirth, and routine gynecological procedures, but they have recently been associated with medically induced abortions and injection drug use. We report 2 fatal cases, one of which was associated with minor trauma, and the other of which was associated with normal childbirth, and we summarize the clinical features of 43 additional cases of reported C. sordellii infection. Of these 45 cases, 8 (18%) were associated with normal childbirth, 5 (11%) were associated with medically induced abortion, and 2 (0.4%) were associated with spontaneous abortion. The case-fatality rate was 100% in these groups. Ten (22%) of the C. sordellii infections occurred in injection drug users, and 50% of these patients died. Other cases of C. sordellii infection (in 19 patients [43%]) occurred after trauma or surgery, mostly in healthy persons, and 53% these patients died. Overall, the mortality rate was 69% (31 of 45 patients). Eighty-five percent of all patients with fatal cases died within 2-6 days of initial infection, and nearly 80% of fatal cases developed leukemoid reactions. Rapid diagnostic tests and improved treatments are needed to reduced the morbidity and mortality associated with this devastating infection. (+info)
Infection of internal umbilical remnant in foals by Clostridium sordellii.
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Omphalitis and the resulting septicemia contribute to perinatal mortality in several animal species. In foals, the most important causes of omphalitis are Escherichia coli and Streptococcus zooepidemicus. However to date, no information has been published about the role of Clostridium sordellii in these infections. In this paper, we describe 8 cases of perinatal mortality in foals associated with internal umbilical remnant infection by C. sordellii. The foals studied were between 12 and 21 days old at the time of death, and various breeds were represented in the group. Five of the foals were male and 3 were female. The diagnosis was established on the basis of the detection of C. sordellii by 3 methods (culture, fluorescent antibody test, and immunohistochemistry) and on gross and histopathologic findings. All foals had acute peritonitis, and the internal umbilical remnant was thickened by edema, hemorrhage, and fibrosis. A moderate amount of serosanguinous fluid with fibrin strands was present in the pericardial sac and pleural cavity. Histopathologically, the urachus and umbilical arterial walls were thickened by edema and exhibited hemorrhage, fibrin, and leukocytic infiltration. Gram-positive bacterial rods were observed in subepithelial areas of the urachus, the adventicia of umbilical arteries, and interstitium of the internal umbilical remnant. On the basis of these findings, we suggest that C. sordellii should be considered in the differential diagnosis for infections of the internal umbilical remnant in foals. (+info)
The leukemoid reaction in Clostridium sordellii infection: neuraminidase induction of promyelocytic cell proliferation.
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Life-threatening Clostridium sordellii infections have recently been reported in women undergoing therapeutic abortion, during natural childbirth, and in injection drug users. Shock, diffuse capillary leak, and a leukemoid reaction (LR) are cardinal features of these infections. The magnitude of the LR is highly correlated with mortality. We have isolated a 42-kDa extractable protein from C. sordellii culture supernatant that stimulates proliferation of promyelocytic HL-60 cells in vitro. Using mass spectrometry, we have identified this protein as the C. sordellii neuraminidase, NanS. Recombinant NanS (rNanS) dose dependently stimulated HL-60 cell proliferation. Increased proliferation was observed when HL-60 cells were cocultured with both rNanS and granulocyte-macrophage colony stimulating factor. In addition, NanS also modified vascular cell adhesion molecule 1, which orchestrates the release of mature and immature granulocytes from bone marrow stromal cells. Thus, neuraminidase likely plays an important role in the characteristic LR in C. sordellii infection. (+info)
The large clostridial toxins from Clostridium sordellii and C. difficile repress glucocorticoid receptor activity.
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We have previously shown that Bacillus anthracis lethal toxin represses glucocorticoid receptor (GR) transactivation. We now report that repression of GR activity also occurs with the large clostridial toxins produced by Clostridium sordellii and C. difficile. This was demonstrated using a transient transfection assay system for GR transactivation. We also report that C. sordellii lethal toxin inhibited GR function in an ex vivo assay, where toxin reduced the dexamethasone suppression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). Furthermore, the glucocorticoid antagonist RU-486 in combination with C. sordellii lethal toxin additively prevented glucocorticoid suppression of TNF-alpha. These findings corroborate the fact that GR is a target for the toxin and suggest a physiological role for toxin-associated GR repression in inflammation. Finally, we show that this repression is associated with toxins that inactivate p38 mitogen-activated protein kinase (MAPK). (+info)