Pathophysiology of Mifepristone-Induced Septic Shock Due to <i>Clostridium sordellii</i>

Miech, Ralph P.

doi:10.1345/aph.1g189

Cited by 54 publications

(26 citation statements)

References 43 publications

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“…Clostridium sordellii is known to cause lethal infections in animals and humans, including in women undergoing medically induced abortions with mifepristone-misoprostol (5,31). Incidences of C. sordellii infections in intravenous heroin users have also been reported (32).…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Clostridium sordellii Toxin Gene Regulator

Reddy

Girinathan

Zapotocny

et al. 2013

Journal of Bacteriology

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Toxigenic Clostridium sordellii causes uncommon but highly lethal infections in humans and animals. Recently, an increased incidence of C. sordellii infections has been reported in women undergoing obstetric interventions. Pathogenic strains of C. sordellii produce numerous virulence factors, including sordellilysin, phospholipase, neuraminidase, and two large clostridial glucosylating toxins, TcsL and TcsH. Recent studies have demonstrated that TcsL toxin is an essential virulence factor for the pathogenicity of C. sordellii. In this study, we identified and characterized TcsR as the toxin gene (tcsL) regulator in C. sordellii. Highthroughput sequencing of two C. sordellii strains revealed that tcsR lies within a genomic region that encodes TcsL, TcsH, and TcsE, a putative holin. By using ClosTron technology, we inactivated the tcsR gene in strain ATCC 9714. Toxin production and tcsL transcription were decreased in the tcsR mutant strain. However, the complemented tcsR mutant produced large amounts of toxins, similar to the parental strain. Expression of the Clostridium difficile toxin gene regulator tcdR also restored toxin production to the C. sordellii tcsR mutant, showing that these sigma factors are functionally interchangeable. Clostridium sordellii, an anaerobic, Gram-positive, spore-forming bacterium, is a common inhabitant of soil and the animal gastrointestinal tract. Virulent strains of C. sordellii are recognized as the causative agents of a broad spectrum of human diseases, including myonecrosis, uterine infections, and sepsis. C. sordellii is also known to cause lethal infections in several animal species, including sheep, foals, and lambs (1-4). Recently, fatal cases of C. sordellii endometritis following medical abortions caused by mifepristone-misoprostol combinations have been reported (5). It has been suggested that mifepristone-misoprostol may facilitate colonization of C. sordellii in uterine tissue, trigger toxin expression, and induce hypotension and systemic shock by deregulating the host's immune response (6).Pathogenic C. sordellii strains produce up to seven identified exotoxins (7). Of these, the two major toxins, lethal toxin (TcsL) and the hemorrhagic toxin (TcsH), are regarded as major virulence factors (8, 9). The lethal toxin produced by C. sordellii was shown to evoke enteritis in animals and proved essential for the virulence of C. sordellii (9, 10). TcsH and TcsL are members of the large clostridial cytotoxin (LCC) family, with predicted molecular masses of 300 kDa and 250 kDa, respectively (8, 9). The C. sordellii toxins were reported to be similar to Clostridium diffcile toxins A and B, both in terms of biological activity and antigenicity (11). To date, only the TcsL-encoding gene has been sequenced; it was found to be 76% identical to the C. difficile toxin B gene (tcdB).In this study, we sequenced two C. sordellii strains, ATCC 9714 and VPI 9048, by high-throughput techniques, and we identified many open reading frames (ORFs) surrounding the tcsL gene. Consistent with pr...

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Clostridium sordellii Toxin Gene Regulator

Reddy

Girinathan

Zapotocny

et al. 2013

Journal of Bacteriology

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“…The anti-progesterone/anti-glucocorticoid agent mifepristone has also been suggested as a putative factor in C. sordellii infection after abortion (4). In addition to causing cervical dilatation and loss of the protective cervical mucous plug, mifepristone evokes decidual ischemia and tissue necrosis, providing access and a ripe milieu for anaerobic bacteria.…”

Section: Discussionmentioning

confidence: 99%

Misoprostol Impairs Female Reproductive Tract Innate Immunity against Clostridium sordellii

Aronoff

Hao

Chung

et al. 2008

The Journal of Immunology

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Fatal cases of acute shock complicating Clostridium sordellii endometritis following medical abortion with mifepristone (also known as RU-486) used with misoprostol were reported. The pathogenesis of this unexpected complication remains enigmatic. Misoprostol is a pharmacomimetic of PGE2, an endogenous suppressor of innate immunity. Clinical C. sordellii infections were associated with intravaginal misoprostol administration, suggesting that high misoprostol concentrations within the uterus impair immune responses against C. sordellii. We modeled C. sordellii endometritis in rats to test this hypothesis. The intrauterine but not the intragastric delivery of misoprostol significantly worsened mortality from C. sordellii uterine infection, and impaired bacterial clearance in vivo. Misoprostol also reduced TNF-α production within the uterus during infection. The intrauterine injection of misoprostol did not enhance mortality from infection by the vaginal commensal bacterium Lactobacillus crispatus. In vitro, misoprostol suppressed macrophage TNF-α and chemokine generation following C. sordellii or peptidoglycan challenge, impaired leukocyte phagocytosis of C. sordellii, and inhibited uterine epithelial cell human β-defensin expression. These immunosuppressive effects of misoprostol, which were not shared by mifepristone, correlated with the activation of the Gs protein-coupled E prostanoid (EP) receptors EP2 and EP4 (macrophages) or EP4 alone (uterine epithelial cells). Our data provide a novel explanation for postabortion sepsis leading to death and also suggest that PGE2, in which production is exaggerated within the reproductive tract during pregnancy, might be an important causal determinant in the pathogenesis of more common infections of the gravid uterus.

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“…Hemorrhagic enteritis occurs in sheep, cattle, and foals after ingestion of C. sordellii spores (2,9,23,36). Penetrating trauma, injection of black tar heroin, and gynecological procedures are potential risk factors for infection in humans (1,27,31,50). Septic shock due to C. sordellii bacteremia results in 70% to 100% mortality rates (1,4).…”

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confidence: 99%

Progesterone Analogs Influence Germination of Clostridium sordellii and Clostridium difficile Spores In Vitro

et al. 2011

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Clostridium sordellii and Clostridium difficile are closely related anaerobic Gram-positive, spore-forming human pathogens. C. sordellii and C. difficile form spores that are believed to be the infectious form of these bacteria. These spores return to toxin-producing vegetative cells upon binding to small molecule germinants. The endogenous compounds that regulate clostridial spore germination are not fully understood. While C. sordellii spores require three structurally distinct amino acids to germinate, the occurrence of postpregnancy C. sordellii infections suggests that steroidal sex hormones might regulate its capacity to germinate. On the other hand, C. difficile spores require taurocholate (a bile salt) and glycine (an amino acid) to germinate. Bile salts and steroid hormones are biosynthesized from cholesterol, suggesting that the common sterane structure can affect the germination of both C. sordellii and C. difficile spores. Therefore, we tested the effect of sterane compounds on C. sordellii and C. difficile spore germination. Our results show that both steroid hormones and bile salts are able to increase C. sordellii spore germination rates. In contrast, a subset of steroid hormones acted as competitive inhibitors of C. difficile spore germination. Thus, even though C. sordellii and C. difficile are phylogenetically related, the two species' spores respond differently to steroidal compounds.

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Pathophysiology of Mifepristone-Induced Septic Shock Due to Clostridium sordellii

Cited by 54 publications

References 43 publications

Identification and Characterization of Clostridium sordellii Toxin Gene Regulator

Identification and Characterization of Clostridium sordellii Toxin Gene Regulator

Misoprostol Impairs Female Reproductive Tract Innate Immunity against Clostridium sordellii

Progesterone Analogs Influence Germination of Clostridium sordellii and Clostridium difficile Spores In Vitro

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