The p38 MAPK and JNK Pathways Protect Host Cells against Clostridium perfringens Beta-Toxin

Nagahama, Masahiro; Shibutani, Masahiro; Seike, Soshi; Yonezaki, Mami; Takagishi, Teruhisa; Oda, Masataka; Kobayashi, Kazuo; Sakùrai, Jun

doi:10.1128/iai.00579-13

Cited by 37 publications

(46 citation statements)

References 33 publications

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“…Beta-toxin induces swelling and lysis of the lymphocytic HL60 cell line, which are preceded by toxin oligomer formation (hexamer or heptamer) in membrane lipid rafts, K + efflux, and Ca ++ , Na + , and Clinfluxes [143,144]. The betadependent K + loss in HL60 was found to trigger the activation of the p38 and JNK MAPK pathways which could have a protective effect of host cell [145]. When injected intradermally, Beta-toxin induces oedema and dermonecrosis, which seem to be mediated by stimulation of sensory nerves containing tachykinins such as substance P and release of tumor [143,144].…”

Section: -Mode Of Actionmentioning

confidence: 99%

Clostridial pore-forming toxins: Powerful virulence factors

Popoff

2014

Anaerobe

106

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Pore formation is a common mechanism of action for many bacterial toxins. More than one third of clostridial toxins are pore-forming toxins (PFTs) belonging to the β-PFT class. They are secreted as soluble monomers rich in β-strands, which recognize a specific receptor on target cells and assemble in oligomers. Then, they undergo a conformational change leading to the formation of a β-barrel, which inserts into the lipid bilayer forming functional pore. According to their structure, clostridial β-PFTs are divided into several families. Clostridial cholesterol-dependent cytolysins form large pores, which disrupt the plasma membrane integrity. They are potent virulence factors mainly involved in myonecrosis. Clostridial heptameric β-PFTs (aerolysin family and staphylococcal α-hemolysin family) induce small pores which trigger signaling cascades leading to different cell responses according to the cell types and toxins. They are mainly responsible for intestinal diseases, like necrotic enteritis, or systemic diseases/toxic shock from intestinal origin. Clostridial intracellularly active toxins exploit pore formation through the endosomal membrane to translocate the enzymatic component or domain into the cytosol. Single chain protein toxins, like botulinum and tetanus neurotoxins, use hydrophobic α-helices to form pores, whereas clostridial binary toxins encompass binding components, which are structurally and functionally related to β-PFTs, but which have acquired the specific activity to internalize their corresponding enzymatic components. Structural analysis suggests that β-PFTs and binding components share a common evolutionary origin.

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Section: -Mode Of Actionmentioning

confidence: 99%

Clostridial pore-forming toxins: Powerful virulence factors

Popoff

2014

Anaerobe

106

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“…Here we show that CD31 functions as the membrane receptor for CPB, a highly potent β-PFT that plays a major role in C. perfringens type C induced fatal necro-hemorrhagic enteritis in animals and humans. Previously, it has been shown that CPB is toxic to endothelial cells, platelets and several cultured monocytic, promyelocytic, lymphoblastic and Blymphocytic cell lines (Nagahama et al, 2013;Shatursky et al, 2000;Steinthorsdottir et al, 2000;Thiel et al, 2017). Our own in vivo studies suggested that vascular endothelial cells in the small intestinal wall are the primary target for this toxin (Gurtner et al, 2010;Miclard et al, 2009a;Miclard et al, 2009b;Popescu et al, 2011;Schumacher et al, 2013).…”

Section: Discussionmentioning

confidence: 81%

“…In vitro, human and porcine endothelial cells and thrombocytes are highly sensitive to CPB (Gurtner et al, 2010;Popescu et al, 2011;Thiel et al, 2017). Other cells with reported in vitro sensitivity to CPB are monocytic, lymphoblastic and lymphocytic cell lines, however the biological role of targeting similar cells in vivo has not been elucidated yet (Nagahama et al, 2003;Nagahama et al, 2013). Intestinal and many other epithelial as well as mesenchymal cells are insensitive to CPB (Gurtner et al, 2010;Manich et al, 2008;Nagahama et al, 2003;Popescu et al, 2011;Roos et al, 2015;Shatursky et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Cell-specific targeting byClostridium perfringensβ-toxin unraveled: the role of CD31 as the toxin receptor

Bruggisser

Tarek

Wyder

et al. 2019

Preprint

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Clostridium perfringens β-toxin (CPB) is a highly active hemolysin β-pore forming toxin and the essential virulence factor for a severe, necro-hemorrhagic enteritis in animals and humans. In vivo and in vitro it exerts a remarkable cell type specificity towards endothelial cells, platelets and some leucocytic cell lines. The target cell specificity of CPB is, however, poorly understood and a receptor explaining this selective toxicity has not been identified. This has hampered further research into the pathogenesis of C. perfringens type C induced enteritis. Here we identify Platelet Endothelial Cell Adhesion Molecule-1 (CD31 or PECAM-1) as the specific membrane receptor for CPB on endothelial cells. CD31 expression is essential for CPB toxicity in endothelial cells and lethality in mice and sufficient to render previously resistant cells highly susceptible to the toxin. We further demonstrate, that the extracellular membrane proximal Ig6 domain of CD31 is required for the interaction with CPB and that expression of CD31 corresponds with the specificity of the toxin towards cultured cell lines. Our results thus provide an explanation for the cell type specificity of CPB and can be linked to the characteristic lesions observed a devastating enteric disease in animals and humans.

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“…P38 mitogen-activated protein kinase (MAPK) is an important factor in host defense against diverse bacterial pore-forming toxins ( 17 – 19 ) and is activated in a pneumolysin-dependent manner in both epithelial cells ( 20 ) and macrophages ( 21 ). To investigate whether p38 MAPK detection of pneumolysin affects cytosolic access, we treated BMMs with SB203580, an inhibitor of p38 MAPK activation (MAPKi), before infection with S. pneumoniae and subcellular fractionation.…”

Section: Resultsmentioning

confidence: 99%

Degradation Products of the Extracellular Pathogen Streptococcus pneumoniae Access the Cytosol via Its Pore-Forming Toxin

Lemon

Weiser

2015

mBio

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Streptococcus pneumoniae is a leading pathogen with an extracellular lifestyle; however, it is detected by cytosolic surveillance systems of macrophages. The innate immune response that follows cytosolic sensing of cell wall components results in recruitment of additional macrophages, which subsequently clear colonizing organisms from host airways. In this study, we monitored cytosolic access by following the transit of the abundant bacterial surface component capsular polysaccharide, which is linked to the cell wall. Confocal and electron microscopy visually characterized the location of cell wall components in murine macrophages outside membrane-bound organelles. Quantification of capsular polysaccharide through cellular fractionation demonstrated that cytosolic access of bacterial cell wall components is dependent on phagocytosis, bacterial sensitivity to the host’s degradative enzyme lysozyme, and release of the pore-forming toxin pneumolysin. Activation of p38 mitogen-activated protein kinase (MAPK) signaling is important for limiting access to the cytosol; however, ultimately, these are catastrophic events for both the bacteria and the macrophage, which undergoes cell death. Our results show how expression of a pore-forming toxin ensures the death of phagocytes that take up the organism, although cytosolic sensing results in innate immune detection that eventually allows for successful host defense. These findings provide an example of how cytosolic access applies to an extracellular microbe and contributes to its pathogenesis.Importance Streptococcus pneumoniae (the pneumococcus) is a bacterial pathogen that is a leading cause of pneumonia. Pneumococcal disease is preceded by colonization of the nasopharynx, which lasts several weeks before being cleared by the host’s immune system. Although S. pneumoniae is an extracellular microbe, intracellular detection of pneumococcal components is critical for bacterial clearance. In this study, we show that following bacterial uptake and degradation by phagocytes, pneumococcal products access the host cell cytosol via its pore-forming toxin. This phenomenon of cytosolic access results in phagocyte death and may serve to combat the host cells responsible for clearing the organism. Our results provide an example of how intracellular access and subsequent immune detection occurs during infection with an extracellular pathogen.

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The p38 MAPK and JNK Pathways Protect Host Cells against Clostridium perfringens Beta-Toxin

Cited by 37 publications

References 33 publications

Clostridial pore-forming toxins: Powerful virulence factors

Clostridial pore-forming toxins: Powerful virulence factors

Cell-specific targeting byClostridium perfringensβ-toxin unraveled: the role of CD31 as the toxin receptor

Degradation Products of the Extracellular Pathogen Streptococcus pneumoniae Access the Cytosol via Its Pore-Forming Toxin

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