Actinobacillus actinomycetemcomitans leukotoxin forms large conductance, voltage-gate ion channels when incorporated into planar lipid bilayers

Lear, James D.; Furblur, Uchena G.; Lally, Edward T.; Tanaka, Jacqueline C.

doi:10.1016/0005-2736(95)00086-i

Cited by 40 publications

(36 citation statements)

References 28 publications

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“…The authors interpreted this result by implying that the aqueous form of the toxin will not spontaneously incorporate into a bilayer, but if the toxin is partially unfolded, as likely happens at the lipid monolayer-water interface, insertion into the membrane occurs and channels are formed. These are also consistent with LTX being required to interact with a cell surface receptor in order to facilitate toxin activation [93,103]. It has been shown that this receptor is the human β2-integrin LFA-1, expressed on immune cell surfaces matching the profile of cytolytic targets [101].…”

Section: Pore Formationsupporting

confidence: 68%

How Mannheimia haemolytica defeats host defence through a kiss of death mechanism

2005

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-Mannheimia haemolytica induced pneumonias are only observed in goats, sheep and cattle. The bacterium produces several virulence factors,whose principal ones are lipopolysaccharide and leukotoxin. The latter is cytotoxic only for ruminant leukocytes, a phenomenon that is correlated with its ability to bind and interact with the ruminant β2-integrin Lymphocyte Function-associated Antigen 1. This paper globally reviews all the information available on host-pathogen interactions underlying respiratory mannheimiosis (formerly pasteurellosis), from the stable and the Petri dish to the biochemical cascade of events triggered by the leukotoxin inside ruminant leukocytes. One conclusion can be made: the most widespread cattle respiratory disease with the most important impact on beef production worldwide, is probably due to a tiny ruminant-specific focal variation in the CD18-and/or CD11a-expressing genes.

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Section: Pore Formationsupporting

confidence: 68%

How Mannheimia haemolytica defeats host defence through a kiss of death mechanism

2005

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“…S2 in the supplemental material). LtxA is an RTX toxin, and it is still debated whether it forms actual pores in biological membranes (50)(51)(52)(53). Peculiarly, we could demonstrate that LtxA releases ATP from phospholipid-1-palmitoyl-2-oleoyl-phosphatidyl choline (POPC) vesicles with kinetics quite similar to those of HlyA.…”

Section: P2y Receptors In the Atp-induced [Camentioning

confidence: 81%

Inhibition of P2X Receptors Protects Human Monocytes against Damage by Leukotoxin from Aggregatibacter actinomycetemcomitans and α-Hemolysin from Escherichia coli

et al. 2016

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␣-Hemolysin (HlyA) from Escherichia coli and leukotoxin A (LtxA) from Aggregatibacter actinomycetemcomitans are important virulence factors in ascending urinary tract infections and aggressive periodontitis, respectively. The extracellular signaling molecule ATP is released immediately after insertion of the toxins into plasma membranes and, via P2X receptors, is essential for the erythrocyte damage inflicted by these toxins. Moreover, ATP signaling is required for the ensuing recognition and phagocytosis of damaged erythrocytes by the monocytic cell line THP-1. Here, we investigate how these toxins affect THP-1 monocyte function. We demonstrate that both toxins trigger early ATP release and a following increase in the intracellular receptors markedly reduces toxin-induced cytolysis. This pattern is paralleled in freshly isolated human monocytes from healthy volunteers. Interestingly, only a minor fraction of the toxin-damaged THP-1 monocytes eventually lyse. P2X 7 receptor inhibition generally prevents cell damage, except from a distinct cell shrinkage that prevails in response to the toxins. Moreover, we find that preexposure to HlyA preserves the capacity of THP-1 monocytes to phagocytose damaged erythrocytes and may induce readiness to discriminate between damaged and healthy erythrocytes. These findings suggest a new pharmacological target for protecting monocytes during exposure to poreforming cytolysins during infection or injury.␣ -Hemolysin (HlyA) is an important virulence factor frequently produced by strains of pathogenic Escherichia coli (1-3). The frequency with which HlyA-producing E. coli strains are isolated from patients increases with severity of the disease (for a review, see reference 2). HlyA is a pore-forming repeat in toxin (RTX) family member which inserts itself receptor independently into cell membranes (1). The cytotoxic effect of HlyA is massively amplified by ATP release, presumably through the HlyA pore (4) and following P2X receptor activation (5, 6). In erythrocytes, P2X 1 and P2X 7 receptors have been implicated in HlyA-induced hemolysis, and blocking of either of these receptors substantially reduces the hemolysis (5, 6). Interestingly, insertion of a HlyA pore does not cause immediate cell swelling and rupture but initially triggers a significant volume reduction that results from an increase in the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) followed by activation of the Ca 2ϩ -sensitive K ϩ and Cl Ϫ channels K Ca 3.1 and TMEM16A (7). During erythrocyte shrinkage, cells expose phosphatidyl serine (PS) in the outer plasma membrane leaflet (7). Recently, we discovered that THP-1 monocytes are more likely to recognize and phagocytose erythrocytes that have been exposed to HlyA (8). This phagocytosis is prevented if HlyA-induced cell damage is diminished by P2X receptor antagonists or if cell shrinkage and PS exposure are blocked (8).Leukotoxin A (LtxA) is a virulence factor often released from Aggregatibacter actinomycetemcomitans in the periodontal connective tissue (9-11). ...

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“…It should be noted, however, that neuraminidase did not abolish the LtxA-induced hemolysis but reduced it by ϳ75%. As LtxA does not insert spontaneously into lipid bilayers (14), this finding could potentially suggest that there may be an alternative binding site in addition to sialic acid. These results have to be evaluated in the light of the one-hit model for toxin-induced hemolysis, which provides proof for a single toxin molecule being enough to lyse one erythrocyte (58).…”

mentioning

confidence: 94%

“…The molecular characteristics of RTX toxins include the presence of glycine-rich nonapeptide repeats, which bind Ca 2ϩ and play a role in the interaction with the host cell surface (10)(11)(12). While LtxA has been assumed to cause cell lysis by formation of hydrophilic membrane pores (13,14), a recent study has argued against pore formation and suggested that LtxA may cause lysis through membrane destabilization (15). The toxin specifically kills leukocytes, particularly polymorphonuclear leukocytes and macrophages from humans, the great apes, and Old World monkeys (16)(17)(18).…”

mentioning

confidence: 99%

Sialic Acid Residues Are Essential for Cell Lysis Mediated by Leukotoxin from Aggregatibacter actinomycetemcomitans

et al. 2014

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c Leukotoxin (LtxA) from Aggregatibacter actinomycetemcomitans is known to target and lyse ␤ 2 -integrin-expressing cells such as polymorphonuclear leukocytes and macrophages. LtxA is an important virulence factor that facilitates chronic inflammation and is strongly associated with a fast-progressing form of periodontitis caused by the JP2 clone of the bacterium. Here, we show that sialic acid residues are important for LtxA-induced cell lysis, regardless of whether the cell express ␤ 2 -integrin or not. Clearly, removal of sialic acid groups significantly reduces a ␤ 2 -integrin-specific LtxA-induced lysis. Moreover, sialic acid presented on alternative proteins, such as, for instance, on erythrocytes that do not express ␤ 2 -integrin, also makes the cells more sensitive to LtxA. The data also illustrate the importance of the negative charge in order for the sialic acid to associate LtxA with the membrane. Removal of sialic acid is in itself sufficient to significantly reduce the negative charge on the erythrocytes. Moreover, we found that on human erythrocytes there is a positive association between the sensitivity to LtxA and the amount of negative charge caused by sialic acid. Interestingly, these features are not shared by all RTX toxins, since ␣-hemolysin from Escherichia coli induced cell lysis of both ␤ 2 -integrin-expressing and nonexpressing cells and this lysis is independent of the presence of sialic acid residues. In conclusion, LtxA not only is cytotoxic to ␤ 2 -integrin-expressing cells but can potentially initiate cell lysis in all cells that present a sufficient density of sialic acid groups on their plasma membrane.

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Actinobacillus actinomycetemcomitans leukotoxin forms large conductance, voltage-gate ion channels when incorporated into planar lipid bilayers

Cited by 40 publications

References 28 publications

How Mannheimia haemolytica defeats host defence through a kiss of death mechanism

How Mannheimia haemolytica defeats host defence through a kiss of death mechanism

Inhibition of P2X Receptors Protects Human Monocytes against Damage by Leukotoxin from Aggregatibacter actinomycetemcomitans and α-Hemolysin from Escherichia coli

Sialic Acid Residues Are Essential for Cell Lysis Mediated by Leukotoxin from Aggregatibacter actinomycetemcomitans

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