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Journal, IO biomarker: Neutralizing Staphylococcus aureus Virulence with AZD6389, a Three mAb Combination, Accelerates Closure of a Diabetic Polymicrobial Wound. (Pubmed Central) - Jul 2, 2022
Treatment with AZD6389, a three-monoclonal antibody combination targeting S. aureus alpha toxin, 4 secreted leukotoxins, and fibrinogen binding cell-surface adhesin clumping factor A resulted in full skin re-epithelization 21 days after inoculation...Here we show in a diabetic mouse wound model that targeting some specific S. aureus virulence factors with a multimechanistic antibody combination accelerated wound closure and promoted full skin re-epithelization. This work opens promising new avenues for the treatment of DFU.
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Journal: Antigenic landscapes on Staphylococcus aureus pore-forming toxins reveal insights into specificity and cross-neutralization. (Pubmed Central) - Jun 23, 2022
We further compared these antigen-specific mAbs to two broadly neutralizing mAbs, H5 (targets Hla, LukSF-PV, HlgAB, HlgCB, and LukED) and SA185 (targeting LukSF-PV, HlgAB, and LukED), and identified molecular level markers for broad-spectrum reactivity among the pore-forming toxins by HDX-MS. To further underscore the need to target the cross-reactive epitopes on leukocidins for the development of broad-spectrum therapies, we annotated Hla sequences isolated from patients in multiple countries for genomic variations within the perspective of our defined epitopes.
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Preclinical, Journal: Hyperimmune Targeting Staphylococcal Toxins Effectively Protect Against USA 300 MRSA Infection in Mouse Bacteremia and Pneumonia Models. (Pubmed Central) - Jun 8, 2022
Staphylococcus aureus has been acquiring multiple drug resistance and has evolved into superbugs such as Methicillin/Vancomycin-resistant S. aureus (MRSA/VRSA) and, consequently, is a major cause of nosocomial and community infections associated with high morbidity and mortality for which no FDA-approved vaccines or biotherapeutics are available...F(ab') also exhibited cross-neutralization titers against three leukotoxins (HlgAB, HlgCB, and LukED) and four SAgs (SEC1, SED, SEK, and SEQ) which were not part of IBT-V02...In vivo efficacy data generated in bacteremia and pneumonia models using USA300 S. aureus strain demonstrated dose-dependent protection by F(ab'). These efficacy data confirmed the staphylococcal toxins as viable targets and support the further development effort of hyperimmune products as a potential adjunctive therapy for emergency uses against life-threatening S. aureus infections.
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Human Anti-Staphylococcus Aureus Antibodies Bind and Neutralize Distantly Related LukAB Variants by Targeting a Conserved Antigenic Site (Exhibit and Poster Hall) - Jun 4, 2022 - Abstract #ASMMicrobe2022ASM_Microbe_3167;
The two-component leukotoxin, LukAB, is critical for S. aureus targeting and killing of human neutrophils and is abundantly produced in the setting of invasive human infection...Several of these mAbs target a conserved site on the LukAB heterodimer important for antibody-mediated toxin neutralization across diverse strains of S. aureus. These data provide additional support for LukAB as a target of intervention, and accounting for S. aureus strain diversity via conserved targets is crucial for a broadly effective intervention strategy.
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Review, Journal: Periodontitis in First Degree-Relatives of Individuals With Rheumatoid Arthritis: A Short Narrative Review. (Pubmed Central) - May 24, 2022
Aggregatibacter actinomycetemcomitans and its leukotoxin A (LtxA), also induces hypercitrullination in host neutrophils...Based on those mechanisms periodontal disease seems to be presented as one of the factors triggering RA in FDR-RA. Larger studies evaluating all the potential mechanisms linking RA and periodontitis are needed in FDR-RA to confirm that periodontal disease should be considered in the screening of FDR-RA.
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Journal: Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxins. (Pubmed Central) - Apr 15, 2022
Then, by combining previous and novel experimental data with protein docking, classical and accelerated weight histogram (AWH) molecular dynamics we propose models of the ACKR1-LukE and CCR5-LukE complexes. This work provides novel insights into chemokine receptor recognition by leukotoxins and suggests that the conserved sulfotyrosine binding pocket could be a target of choice for future drug development.
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Journal: Discrepancies in Antimicrobial Susceptibility between the JP2 and the Non-JP2 Genotype of Aggregatibacter actinomycetemcomitans. (Pubmed Central) - Mar 26, 2022
The Aggregatibacter actinomycetemcomitans JP2 genotype is associated with high leukotoxin production and severe (aggressive) periodontitis...Cefotaxime, meropenem, levofloxacin, and trimethoprim-sulfamethoxazole MICs were all ≤0.25 mg/L, while MIC values for amoxicillin, azithromycin and tetracycline were 1 mg/L...The discrepant findings indicate that A. actinomycetemcomitans may be divided into two separate wild types, with a suggested intrinsic reduced susceptibility for benzylpenicillin in the majority of non-JP2 genotype strains. Possible implications for the treatment of A. actinomycetemcomitans infections are discussed.
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Clinical, Journal: Impaired T lymphocyte responses during childhood Staphylococcus aureus infection. (Pubmed Central) - Feb 24, 2022
In addition, LtxA stimulated differentiation towards osteoclasts-like cells in LPS-treated THP-1 cells. These findings identify a potential mechanism by which S. aureus infection actively evades adaptive immune responses, thereby preventing the development of protective immunty and maintaining susceptibility to recurrent infection.
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Preclinical, Journal: Single-Chain Fragment Variables Targeting Leukocidin ED Can Alleviate the Inflammation of Staphylococcus aureus-Induced Mastitis in Mice. (Pubmed Central) - Feb 4, 2022
In our previous studies, leukotoxin ED (LukED) was detected in most S. aureus strains isolated from bovine mastitis...The ELISA and qPCR assays showed that scFvs reduced the transcription and expression levels of Tumor Necrosis Factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8 and IL-18 (p < 0.05). The overall results demonstrated the protective anti-inflammatory effect of scFvs in vitro and in vivo, enlightening the potential role of scFvs in the prevention and treatment of S. aureus-induced mastitis.
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Journal: Molecular insights into mechanisms of GPCR hijacking by Staphylococcus aureus. (Pubmed Central) - Dec 22, 2021
Unexpectedly, hydrogen/deuterium exchange mass spectrometry analysis revealed that toxin binding allosterically modulates the intracellular G protein-binding domain of the receptor, resulting in dissociation and/or changes in the architecture of ACKR1-Gαi1 protein complexes observed in living cells. Altogether, our study brings important molecular insights into the initial steps of leukotoxins targeting a host GPCR.
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Journal: Protection against Mycoplasma bovis infection in calves following intranasal vaccination with modified-live Mannheimia haemolytica expressing Mycoplasma antigens. (Pubmed Central) - Dec 16, 2021
Novel live vaccine strains of Mannheimia haemolytica serotypes (St)1 and St6, expressing and secreting inactive yet immunogenic leukotoxin (leukotoxoid) fused to antigenic domains of Mycoplasma bovis Elongation Factor Tu (EFTu) and Heat shock protein (Hsp) 70 were constructed and tested for efficacy in cattle...Notably, dramatically decreased lung loads of M. bovis were detected in the vaccinated cattle. These observations indicate that the attenuated M. haemolytica vaccine strains expressing Mycoplasma antigens can control M. bovis infection and disease symptoms in a controlled setting.
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Journal: Leukotoxin (LtxA/Leukothera) induces ATP expulsion via pannexin-1 channels and subsequent cell death in malignant lymphocytes. (Pubmed Central) - Dec 16, 2021
We show that LtxA is able to kill malignant lymphocytes through an apoptotic death pathway which is potentially linked to a Panx1/P2XR mediated necrotic form of death. Thus, inhibition of ATP release appears to significantly delay the onset of LtxA induced apoptosis while completely disabling the necrotic death pathway in T-lymphocytes, demonstrating the crucial role of ATP release in LtxA-mediated cell death.
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Journal: Leukotoxin production by Fusobacterium necrophorum strains in relation to severity of liver abscesses in cattle. (Pubmed Central) - Nov 29, 2021
Across all strains, the correlation coefficients between leukotoxic activity and leukotoxin concentration at 9 and 24 h were 0.14 (P = 0.17) and 0.47 (P < 0.0001), respectively. In conclusion, strains isolated from severe liver abscesses had significantly higher leukotoxic activities and leukotoxin protein concentrations compared to strains isolated from mild liver abscesses.
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Journal: Epigallocatechin gallate alters leukotoxin secretion and Aggregatibacter actinomycetemcomitans virulence. (Pubmed Central) - Nov 10, 2021
The Aa virulence might be reduced through use of W. ugandensis and the high levels of A. aphrophilus. Together, these results demonstrate that EGCg has important, but complicated, effects on toxin secretion and activity; new dosing strategies and comprehensive model systems may be required to properly develop these anti-virulence activities.
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Review, Journal: Staphylococcus lugdunensis: a Skin Commensal with Invasive Pathogenic Potential. (Pubmed Central) - Oct 27, 2021
This differs fundamentally from S. aureus, which actively grows and expresses bicomponent leukotoxins that cause membrane damage and could contribute to survival in the infected host...However, this is contraindicated by its innate virulence. Studies to obtain a deeper understanding of S. lugdunensis colonization, virulence, and microbiome interactions are therefore warranted.
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Journal: Prevalence and distribution of multilocus sequence types of Staphylococcus aureus isolated from bulk tank milk and cows with mastitis in Pennsylvania. (Pubmed Central) - Oct 13, 2021
Two isolates of ST398 showed multidrug resistance (>3 antibiotics) against clindamycin, erythromycin, tetracycline, and penicillin...Most isolates were positive for lukED (95%) and lukAB (96.3%) leukotoxin genes...It was observed that one ST of S. aureus predominated in the herd and this ST can coexist with several other ST types of S. aureus strains. When STs were interpreted along with virulence, leucocidin genes and antimicrobial resistance, ST-variants allowed better interpretation of the S. aureus molecular epidemiologic findings specifically for tracing recurrence or persistence of infections in cow over time, among cows in the herd, and between herds in Pennsylvania.
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Journal: Bi-component HlgC/HlgB and HlgA/HlgB γ-hemolysins from S. aureus: Modulation of Ca channels activity through a differential mechanism. (Pubmed Central) - Oct 6, 2021
Staphylococcal bi-component leukotoxins known as *pore-forming toxins* induce upon a specific binding to membrane receptors, two independent cellular events in human neutrophils...Our findings provide new insights about different mechanisms involved in the staphylococcal γ-hemolysins activity to regulate three different types of Ca-independent Ca channels. We conclude that (i) HlgC/HlgB stimulates the opening of La-sensitive Ca channels, through a cholera toxin-sensitive G protein, (ii) HlgA/HlgB stimulates the opening of Ca channels not sensitive to La, through a G protein-independent process, and (iii) unlike HlgA/HlgB, HlgC/HlgB toxins prevent the opening of a new type of Ca channels by phosphorylation/de-phosphorylation-dependent mechanisms.
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Clinical, Journal: First Report of Antimicrobial Susceptibility and Virulence Gene Characterization Associated with Staphylococcus aureus Carriage in Healthy Camels from Tunisia. (Pubmed Central) - Sep 29, 2021
All isolates harbored different virulence genes, including hld, encoding delta hemolysin; lukE-lukD, encoding bicomponent leukotoxin LukE-LukD; the clfB gene, encoding clumping factor B; the laminin gene, encoding laminin-binding protein; and cap8, encoding capsule type 8...Binding proteins, including collagen (cbp) and elastin-binding protein (ebp), were detected in two S. aureus isolates while fibrinogen-binding protein (fib) was identified in four isolates. This study provides the first set of genotyping data on the population structure and presence of toxin genes of S. aureus strains in Tunisian camels.
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Journal: Expression of virulence factors under different environmental conditions in Aggregatibacter actinomycetemcomitans. (Pubmed Central) - Sep 23, 2021
When HK1651 was grown on agar plates, genes encoding many virulence factors, including the Omps, cytolethal distending toxin, and leukotoxin, were differentially expressed...Coaggregation with Fusobacterium nucleatum was remarkably enhanced using HK1651 grown in the CS-containing medium. Our results indicate that the expression of virulence factors is altered by adaptation to different conditions during infection.
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Journal: Whole Genome Analysis of Environmental Pseudomonas mendocina Strains: Virulence Mechanisms and Phylogeny. (Pubmed Central) - Aug 1, 2021
Nevertheless, this study revealed that P. mendocina possesses an important number of virulence factors, including a leukotoxin, flagella, pili, and the Type 2 and Type 6 Secretion Systems, that could be responsible for their pathogenesis. More phenotypical and in vivo studies are needed to deepen the association with human infections and the potential P. mendocina pathogenicity.
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Journal, IO biomarker: O-Polysaccharide Plays a Major Role on the Virulence and Immunostimulatory Potential of Aggregatibacter actinomycetemcomitans During Periodontal Infection. (Pubmed Central) - Jun 30, 2021
While several studies have provided evidence related to the virulence factors of A. actinomycetemcomitans involved in the host cell death and immune evasion, such as its most studied primate-specific virulence factor, leukotoxin, the role of specific lipopolysaccharide (LPS) domains remain poorly understood...In addition, the O-PS-defective rmlC mutant strain led to impaired activation of antigen-presenting cells, with less expression of the co-stimulatory molecules CD40 and CD80 in B lymphocytes and dendritic cells, and downregulated expression of Tnfa and Il1b in splenocytes. In conclusion, these data demonstrate that the O-PS from the serotype b of A. actinomycetemcomitans plays a key role in the capacity of the bacterium to prime oral innate and adaptive immune responses, by triggering the Th1 and Th17-driven tooth-supporting bone resorption during periodontitis.
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Journal: Staphylococcus aureus Panton-Valentine Leukocidin triggers an alternative NETosis process targeting mitochondria. (Pubmed Central) - Jun 30, 2021
Panton-Valentine Leukocidin (PVL) is a bicomponent leukotoxin produced by 3%-10% of clinical Staphylococcus aureus (SA) strains involved in the severity of hospital and community-acquired infections...PVL NETosis is elicited through Ca -activated SK channels and Myeloperoxidase activity but is abolished by Allopurinol pretreatment of neutrophils...Unexpectedly, PVL NETosis does not seem to involve Src kinases, which is the main kinase family activated downstream the binding of PVL F subunit to CD45 receptor, while the specific kinase pathway differs from the NADPH oxidase-dependent NETosis. PVL alone causes a different and specific form of NETosis that may rather represent a bacterial strategy conceived to disarm and disrupt the immune response, eventually allowing SA to spread.
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Review, Journal: Cytochrome P450-derived linoleic acid metabolites EpOMEs and DiHOMEs: A review of recent studies. (Pubmed Central) - Jun 16, 2021
More recent research has suggested the DiHOMEs may be important lipid mediators in pain perception, altered immune response, and brown adipose tissue (BAT) activation by cold and exercise. The purpose of this review is to summarize the current understanding of the physiological and pathophysiological roles and modes of action of the EpOMEs and DiHOMEs in health and disease.
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Biomarker, Journal: Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections. (Pubmed Central) - Apr 22, 2021
The epoxides of linoleic acid (leukotoxins) regulate skin barrier function, perivascular and alveolar permeability and have been associated with poor outcomes in burn patients and in sepsis...Thus, pathways involved in the biosynthesis and degradation of these regulatory lipids should be investigated in larger biomarker studies to determine their significance in COVID-19 disease. In addition, incorporating diols in plasma multi-omics of patients could illuminate the COVID-19 pathological signature along with other lipid mediators and blood chemistry.
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Journal: Evaluation of the Virulence of Aggregatibacter actinomycetemcomitans Through the Analysis of Leukotoxin. (Pubmed Central) - Mar 25, 2021
The leukotoxin expression is dependent on the upstream sequence, likely including the promoter, of the gene encoding leukotoxin; strains with the truncated/short upstream sequence express more leukotoxin than strains with the general/long upstream. This chapter addresses the determination of the type of the leukotoxin promoter by PCR analysis, and detection of the apoptosis in the coculture of human monocyte cell line (THP-1) with A. actinomycetemcomitans by the DNA ladder formation, membrane perturbation, and lactate dehydrogenase release.
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Clinical, Review, Journal: Etiology of aggressive periodontitis in individuals of African descent. (Pubmed Central) - Mar 20, 2021
actinomycetemcomitans strains isolated from patients with AgP produce leukotoxin (LtxA), which specifically affects polymorphonuclear leukocytes in primates, especially humans...An elevated serum level of IL-17 produced by Th17 cells may be a characteristic of AgP. Analyses of the relationships among bacteria, host defenses, genetic predisposition, and numerous other factors are required to understand the progression of this disease.
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Journal: Lactobacilli Postbiotics reduce biofilm formation and alter transcription of virulence genes of Aggregatibacter actinomycetemcomitans. (Pubmed Central) - Mar 19, 2021
Transcription of cytolethal distending toxin (cdtB) and leukotoxin (ltxA) was downregulated by CFS of LA5 and LR32 CFS...Transcription of dspB was abrogated by LR32 and NCFM CFS, but increased by HN001, whereas expression of pgA was not affected by any postbiotic. Our data indicated the potential of postbiotics from lactobacilli, especially LA5, to reduce colonization levels of Aa to modulate the expression of virulence factors implicated in evasion of host defenses.
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Journal: Leukotoxins. (Pubmed Central) - Mar 3, 2021
There was some suggestion that intermediate concentrations CS may increase cytotoxicity of α hemolysin however further investigation was delayed due to COVID-19. Leukotoxins are the critical virulence factors of several Gram-positive and Gram-negative bacteria [...].
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Journal: Inhibition of protective immunity against Staphylococcus aureus infection by MHC-restricted immunodominance is overcome by vaccination. (Pubmed Central) - Dec 18, 2020
Vaccination with a-toxin or leukotoxin E (LukE) elicited similar antibody and T cell responses in mice expressing H-2 or H-2, but vaccine-elicited responses were inhibited by concomitant infection in H-2-expressing mice...A vaccine that elicited T cell and antibody responses protected mice that expressed H-2 or H-2, demonstrating that vaccination can overcome MHC-restricted immunodominance. Together, these results define how host genetics determine whether immunity elicted by S. aureus is protective and provide a mechanistic roadmap for future vaccine design.
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