Clostridium perfringens Delta-Toxin Induces Rapid Cell Necrosis

Seike, Soshi; Miyamoto, Kazuaki; Kobayashi, Kazuo; Takehara, Masaya; Nagahama, Masahiro

doi:10.1371/journal.pone.0147957

Cited by 20 publications

(21 citation statements)

References 32 publications

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“…Although cell membrane structure is promptly disorganized in necrosis, in apoptosis it is initially kept intact in the early stages [30,33]. This manner of death has also been described as a mechanism of action of several bacterial pore-forming toxins such as Bacillus thuringiensis and Clostridium perfringens delta-toxin [34,35,36].…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Mechanism of Action Involved in Enhanced Suicide Gene Colon Cancer Cell Killer Effect Mediated by Gef and Apoptin

Cáceres¹,

Ramírez

Carrillo

et al. 2019

Cancers

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Despite the great advances in cancer treatment, colorectal cancer has emerged as the second highest cause of death from cancer worldwide. For this type of tumor, the use of suicide gene therapy could represent a novel therapy. We recently demonstrated that co-expression of gef and apoptin dramatically inhibits proliferation of the DLD-1 colon cell line. In the present manuscript, we try to establish the mechanism underlying the enhanced induction of apoptosis by triggering both gef and apoptin expression in colon tumor cells. Scanning microscopy reveals that simultaneous expression of gef and apoptin induces the apparition of many “pores” in the cytoplasmic membrane not detected in control cell lines. The formation of pores induced by the gef gene and accentuated by apoptin results in cell death by necrosis. Moreover, we observed the presence of apoptotic cells. Performing protein expression analysis using western blot, we revealed an activation of mitochondrial apoptosis (increased expression of Pp53, cytochrome c, Bax, and caspase 9) and also the involvement of the extrinsic pathway through caspase 8activation. In conclusion, in this manuscript we demonstrate for the first time that the extrinsic pathway of apoptosis and pore formation is also involved in the cell death caused by the co-expression of the gef and apoptin genes. Our results suggest that co-expression of gef and apoptin genes induces an increase in post-apoptotic necrotic cell death and could be a valuable tool in the design of new antitumor strategies focused on the enhancement of the immune response against cancer cell death.

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Section: Discussionmentioning

confidence: 99%

Deciphering the Mechanism of Action Involved in Enhanced Suicide Gene Colon Cancer Cell Killer Effect Mediated by Gef and Apoptin

Cáceres¹,

Ramírez

Carrillo

et al. 2019

Cancers

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“…The discovery of four newly identified leukotoxin domain-containing proteins, DlpA, LdpA, LdpB and LdpC, emphasises the diversity of this class of protein in C. perfringens . With the recent discovery of NetB, NetE, NetF and NetG [8,10], as well as increased functional work to define the mechanism of action of the toxins, including delta toxin, it has been shown that leukotoxin domain proteins in C. perfringens are largely responsible for virulence and pathogenesis in multiple diseases [8,11,30,31] Characterisation of two epsilon domain proteins, and the characterisation of another protein sequence with similarity to the clostridial binary toxins, suggests that there is also a high amount of genetic variability of these toxins classes, and not just within the leukotoxin domains.…”

Section: Discussionmentioning

confidence: 99%

In silico Identification of Novel Toxin Homologs and Associated Mobile Genetic Elements in Clostridium perfringens

et al. 2019

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Clostridium perfringens causes a wide range of diseases in a variety of hosts, due to the production of a diverse set of toxins and extracellular enzymes. The C. perfringens toxins play an important role in pathogenesis, such that the presence and absence of the toxins is used as a typing scheme for the species. In recent years, several new toxins have been discovered that have been shown to be essential or highly correlated to diseases; these include binary enterotoxin (BecAB), NetB and NetF. In the current study, genome sequence analysis of C. perfringens isolates from diverse sources revealed several putative novel toxin homologs, some of which appeared to be associated with potential mobile genetic elements, including transposons and plasmids. Four novel toxin homologs encoding proteins related to the pore-forming Leukocidin/Hemolysin family were found in type A and G isolates. Two novel toxin homologs encoding proteins related to the epsilon aerolysin-like toxin family were identified in Type A and F isolates from humans, contaminated food and turkeys. A novel set of proteins related to clostridial binary toxins was also identified. While phenotypic characterisation is required before any of these homologs can be established as functional toxins, the in silico identification of these novel homologs on mobile genetic elements suggests the potential toxin reservoir of C. perfringens may be much larger than previously thought.

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“…Recently, using toxin-host interaction system in Caenorhabditis elegans , Cry6Aa was shown to promote cell death through necrotic signaling pathway (Zhang et al, 2016 ). In addition, many bacterial toxins such as β-toxin from Clostridium perfringens , delta-toxin from Clostridium septicum , and VacA from Helicobacter pylori were shown to cause cell necrosis (Knapp et al, 2010 ; Radin et al, 2011 ; Sridharan and Upton, 2014 ; Seike et al, 2016 ). Taken together, the results obtained in the present study confirm that exposure to sub-lethal doses of Cry toxin triggers cell death in larval mid-gut of A. janata through necrosis.…”

Section: Discussionmentioning

confidence: 99%

Larval Mid-Gut Responses to Sub-Lethal Dose of Cry Toxin in Lepidopteran Pest Achaea janata

et al. 2017

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The lack of homogeneity in field application of Bacillus thuringiensis formulation often results in ingestion of sub-lethal doses of the biopesticide by a fraction of pest population and there by promotes the toxin tolerance and resistance in long term. Gut regeneration seems to be one of the possible mechanism by which this is accomplished. However, the existing information is primarily derived from in vitro studies using mid-gut cell cultures. Present study illustrates cellular and molecular changes in mid-gut epithelium of a Bt-susceptible polyphagous insect pest castor semilooper, Achaea janata in response to a Cry toxin formulation. The present report showed that prolonged exposure to sub-lethal doses of Cry toxin formulation has deleterious effect on larval growth and development. Histological analysis of mid-gut tissue exhibits epithelial cell degeneration, which is due to necrotic form of cell death followed by regeneration through enhanced proliferation of mid-gut stem cells. Cell death is demonstrated by confocal microscopy, flow-cytometry, and DNA fragmentation analysis. Cell proliferation in control vs. toxin-exposed larvae is evaluated by bromodeoxyuridine (BrdU) labeling and toluidine blue staining. Intriguingly, in situ mRNA analysis detected the presence of arylphorin transcripts in larval mid-gut epithelial cells. Quantitative PCR analysis further demonstrates altered expression of arylphorin gene in toxin-exposed larvae when compared with the control. The coincidence of enhanced mid-gut cell proliferation coincides with the elevated arylphorin expression upon Cry intoxication suggests that it might play a role in the regeneration of mid-gut epithelial cells.

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Clostridium perfringens Delta-Toxin Induces Rapid Cell Necrosis

Cited by 20 publications

References 32 publications

Deciphering the Mechanism of Action Involved in Enhanced Suicide Gene Colon Cancer Cell Killer Effect Mediated by Gef and Apoptin

Deciphering the Mechanism of Action Involved in Enhanced Suicide Gene Colon Cancer Cell Killer Effect Mediated by Gef and Apoptin

In silico Identification of Novel Toxin Homologs and Associated Mobile Genetic Elements in Clostridium perfringens

Larval Mid-Gut Responses to Sub-Lethal Dose of Cry Toxin in Lepidopteran Pest Achaea janata

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