Receptor-Based Peptides for Inhibition of Leukotoxin Activity

Krueger, Eric; Hayes, Shannon; Chang, En Hyung; Yutuc, Shailagne; Brown, Angela C.

doi:10.1021/acsinfecdis.7b00230

Cited by 19 publications

(27 citation statements)

References 64 publications

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“…Follow-up studies ectopically expressed only CD11A/CD18 in non-susceptible cell lines and Lally et al confirmed the lack of endogenous CD11B and CD11C surface expression on K562 cells, so the conclusions could only be related to the interaction of LtxA with LFA-1. In light of the Reinholdt et al results that LtxA is equally cytotoxic to all β 2 integrin species tested and that direct binding only occurs with the β 2 subunit, the previous identification of the β-propeller region of CD11A as required for LtxA activity and recent results from Krueger et al are seemingly contradictory [26,27].…”

Section: Proposed Receptors On Nucleated Cellsmentioning

confidence: 97%

“…A) LtxA: LFA-1 [24] B) LtxA: CD18 EGF-like domains 2, 3, and 4 within amino acids 500-600 [25] C) LtxA: CD11A β-sheets 1 and 2 of the β-propeller region [26,27] Structural models of LFA-1 and Mac-1, respectively composed of CD11A/CD18 and CD11B/CD18, are shown with labels A through S indicate where potential binding sites for RTX toxins occur, with the published reference for the indicated binding site detailed below.…”

Section: Proposed Receptors On Nucleated Cellsmentioning

confidence: 99%

“…(A) LtxA: LFA-1 [24] (B) LtxA: CD18 EGF-like domains 2, 3, and 4 within amino acids 500-600 [25] (C) LtxA: CD11A β-sheets 1 and 2 of the β-propeller region [26,27] (D) LtxA: CD18 [28,29] (E) LtxA: Activated LFA-1 (m24 epitope) [30] (F) LtxA: CD11A and CD18 cytoplasmic tails [31] (G) LktA: LFA-1 [32][33][34][35][36] (H) LktA: CD18 [32,33,[37][38][39][40] (I) LktA: CD18 EGF-like domain 3 within amino acids 500-600 [41,42] (J) LktA: CD18 amino acids 1-291 [43] (K) LktA: Mac-1 [44] (L) LktA: CD18 uncleaved signal peptide [45] (M) CyaA: Mac-1 [46] (N) CyaA: CD11B (O) CyaA: Activated LFA-1 (m24 epitope) [47] (P) CyaA: CD11B amino acids 614-682 [48] (Q) HlyA: LFA-1 [24] (R) HlyA: extra-cytoplasmic region of CD18 [29] (S) ApxIIIA: CD18 [49] 2.1.1. LtxA…”

Section: Proposed Receptors On Nucleated Cellsmentioning

confidence: 99%

“…Based on the Kieba et al publication, Krueger et al generated peptides which mimic the proposed binding region of LtxA on the CD11A subunit to inhibit LtxA activity [27]. Preincubation of LtxA with the peptides inhibited cytolytic activity on THP-1 cells (human monocytes).…”

Section: Proposed Receptors On Nucleated Cellsmentioning

confidence: 99%

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RTX Toxins Ambush Immunity’s First Cellular Responders

Ristow

Welch

2019

Toxins

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The repeats-in-toxin (RTX) family represents a unique class of bacterial exoproteins. The first family members described were toxins from Gram-negative bacterial pathogens; however, additional members included exoproteins with diverse functions. Our review focuses on well-characterized RTX family toxins from Aggregatibacter actinomycetemcomitans (LtxA), Mannheimia haemolytica (LktA), Bordetella pertussis (CyaA), uropathogenic Escherichia coli (HlyA), and Actinobacillus pleuropneumoniae (ApxIIIA), as well as the studies that have honed in on a single host cell receptor for RTX toxin interactions, the β2 integrins. The β2 integrin family is composed of heterodimeric members with four unique alpha subunits and a single beta subunit. β2 integrins are only found on leukocytes, including neutrophils and monocytes, the first responders to inflammation following bacterial infection. The LtxA, LktA, HlyA, and ApxIIIA toxins target the shared beta subunit, thereby targeting all types of leukocytes. Specific β2 integrin family domains are required for the RTX toxin’s cytotoxic activity and are summarized here. Research examining the domains of the RTX toxins required for cytotoxic and hemolytic activity is also summarized. RTX toxins attack and kill phagocytic immune cells expressing a single integrin family, providing an obvious advantage to the pathogen. The critical question that remains, can the specificity of the RTX-β2 integrin interaction be therapeutically targeted?

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Section: Proposed Receptors On Nucleated Cellsmentioning

confidence: 97%

Section: Proposed Receptors On Nucleated Cellsmentioning

confidence: 99%

Section: Proposed Receptors On Nucleated Cellsmentioning

confidence: 99%

Section: Proposed Receptors On Nucleated Cellsmentioning

confidence: 99%

See 2 more Smart Citations

RTX Toxins Ambush Immunity’s First Cellular Responders

Ristow

Welch

2019

Toxins

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“…Making use of the previous work that demonstrated the domains of CD11a targeted by LtxA (Kieba et al, 2007), we synthesized a series of peptides based on the last β‐strand in the first β‐sheet (W1S4) and all four β‐strands in the second β‐sheet (W2S1–W2S4). We found that four of the five peptides inhibited LtxA cytotoxicity in THP‐1 cells (Krueger, Hayes, Chang, Yutuc, & Brown, 2018). This suggests that the peptides bind to LtxA, and inhibit the toxin's interaction with CD11a on the host cells by occupying the binding site on the toxin.…”

Section: Anti‐ltxa Strategiesmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti‐toxin therapeutics

Krueger

Brown

2020

Molecular Oral Microbiology

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Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium associated with localized aggressive periodontitis, as well as other systemic diseases. This organism produces a number of virulence factors, all of which provide some advantage to the bacterium. Several studies have demonstrated that clinical isolates from diseased patients, particularly those of African descent, frequently belong to specific clones of A. actinomycetemcomitans that produce significantly higher amounts of a protein exotoxin belonging to the repeats-in-toxin (RTX) family, leukotoxin (LtxA), whereas isolates from healthy patients harbor minimally leukotoxic strains. This finding suggests that LtxA might play a key role in A. actinomycetemcomitans pathogenicity. Because of this correlation, much work over the past 30 years has been focused on understanding the mechanisms by which LtxA interacts with and kills host cells.In this article, we review those findings, highlight the remaining open questions, and demonstrate how knowledge of these mechanisms, particularly the toxin's interactions with lymphocyte function-associated antigen-1 (LFA-1) and cholesterol, enables the design of targeted anti-LtxA strategies to prevent/treat disease. K E Y W O R D SAggregatibacter actinomycetemcomitans, leukotoxin, LFA-1, repeats-in-toxin

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Catechin-mediated restructuring of a bacterial toxin inhibits activity

Chang

Huang

Lin

et al. 2019

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background: Catechins, polyphenols derived from tea leaves, have been shown to have antibacterial properties, through direct killing of bacteria as well as through inhibition of bacterial toxin activity. In particular, certain catechins have been shown to have bactericidal effects on the oral bacterium, Aggregatibacter actinomycetemcomitans, as well as the ability to inhibit a key virulence factor of this organism, leukotoxin (LtxA). The mechanism of catechin-mediated inhibition of LtxA has not been shown. Methods: In this work, we studied the ability of six catechins to inhibit LtxA-mediated cytotoxicity in human white blood cells, using Trypan blue staining, and investigated the mechanism of action using a combination of techniques, including fluorescence and circular dichroism spectroscopy, confocal microscopy, and surface plasmon resonance. Results: We found that all the catechins except (−)-catechin inhibited the activity of this protein, with the galloylated catechins having the strongest effect. Pre-incubation of the toxin with the catechins increased the inhibitory action, indicating that the catechins act on the protein, rather than the cell. The secondary structure of LtxA was dramatically altered in the presence of catechin, which resulted in an inhibition of toxin binding to cholesterol, an important initial step in the cytotoxic mechanism of the toxin. Conclusions: These results demonstrate that the catechins inhibit LtxA activity by altering its structure to prevent interaction with specific molecules present on the host cell surface. General Significance: Galloylated catechins modify protein toxin structure, inhibiting the toxin from binding to the requisite molecules on the host cell surface.

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Receptor-Based Peptides for Inhibition of Leukotoxin Activity

Cited by 19 publications

References 64 publications

RTX Toxins Ambush Immunity’s First Cellular Responders

RTX Toxins Ambush Immunity’s First Cellular Responders

Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti‐toxin therapeutics

Catechin-mediated restructuring of a bacterial toxin inhibits activity

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