Human Serum Albumin Binds Streptolysin O (SLO) Toxin Produced by Group A Streptococcus and Inhibits Its Cytotoxic and Hemolytic Effects

Vita, Gian Marco; G, De Simone; Leboffe, Loris; Montagnani, Francesca; Mariotti, Davide; Bella, Stefano Di; Luzzati, Roberto; Gori, Andrea; Ascenzi, Paolo; Masi, Alessandra di

doi:10.3389/fimmu.2020.507092

Cited by 17 publications

(26 citation statements)

References 57 publications

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“…So, while CD toxins and CDI sera suspended in PBS were not detectable with our semi-quantitative dot-blot method, toxins resuspension in the TBS buffer allowed us to overcome this limitation. Notably, both immunoglobulins and albumin are part of humoral immunity, which plays a crucial role in protecting individuals from severe and/or rCDI [ 9 , 24 , 25 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

High Serum Levels of Toxin A Correlate with Disease Severity in Patients with Clostridioides difficile Infection

et al. 2021

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Cloistridioides difficile (CD) represents a major public healthcare-associated infection causing significant morbidity and mortality. The pathogenic effects of CD are mainly caused by the release of two exotoxins into the intestine: toxin A (TcdA) and toxin B (TcdB). CD infection (CDI) can also cause toxemia, explaining the systemic complications of life-threatening cases. Currently, there is a lack of sensitive assays to detect exotoxins circulating in the blood. Here, we report a new semi-quantitative diagnostic method to measure CD toxins serum levels. The dot-blot assay was modified to separately detect TcdA and TcdB in human serum with a limit of detection at the pg/mL levels. TcdA and TcdB concentrations in the plasma of 35 CDI patients were measured at the time of CDI diagnosis and at the fourth and tenth day after CDI diagnosis and initiation of anti-CDI treatment. TcdA and TcdB levels were compared to those determined in nine healthy blood donors. Toxemia was detected in the plasma of 33 out of the 35 CDI cases. We also assessed the relationship between TcdA serum levels and CDI severity, reporting that at the time of CDI diagnosis the proportion of severe CDI cases with a TcdA serum level > 60 pg/µL was higher than in mild CDI cases (29.4% versus 66.6%, p = 0.04). In conclusion, data reported here demonstrate for the first time that toxemia is much more frequent than expected in CDI patients, and specifically that high serum levels of TcdA correlate with disease severity in patients with CDI.

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Section: Discussionmentioning

confidence: 99%

High Serum Levels of Toxin A Correlate with Disease Severity in Patients with Clostridioides difficile Infection

et al. 2021

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“…It has been reported that human serum albumin can bind to SLO with high affinity and neutralizes the cytotoxic effects of SLO (Vita et al, 2020). Therefore, we next investigated the effect of SLO (100 ng/ml) in presence of 1% human serum albumin in vitro.…”

Section: Slo Impairs Endothelium-dependent Vasodilation and Enos Phosphorylationmentioning

confidence: 99%

“…Recently, Vita et al reported that serum albumin protects cells from cytotoxic effects and cell membrane permeabilization induced by SLO (Vita et al, 2020), suggesting the presence of physiologically important buffering system for this toxin. However, our results showed that the impairment of ACh-induced endothelial-dependent relaxation due to SLO was scarcely affected in presence of albumin (Figure 2E).…”

Section: Change In Vascular Functions and Cell Signalingmentioning

confidence: 99%

Streptococcal Exotoxin Streptolysin O Causes Vascular Endothelial Dysfunction Through PKCβ Activation

Mukohda

Nakamura

Takeya

et al. 2021

J Pharmacol Exp Ther

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Streptolysin O (SLO) is produced by common hemolytic streptococci that cause a wide range of diseases from pharyngitis to life-threatening necrotizing fasciitis and toxic shock syndrome. While the importance of SLO in invasive hemolytic streptococcus infection has been well demonstrated, the role of circulating SLO in non-invasive infection remains unclear. The aim of this study was to characterize the pharmacological effect of SLO on vascular functions, focusing on cellular signaling pathways. In control Wistar rats, SLO treatment (1-1000 ng/mL) impaired acetylcholine-induced endothelial-dependent relaxation in the aorta and second-order mesenteric artery in a dose-dependent manner, without any effects on sodium nitroprusside-induced endothelium-independent relaxation or agonist-induced contractions. SLO also increased phosphorylation of the endothelial NO synthase (eNOS) inhibitory site at Thr495 in the aorta. Pharmacological analysis indicated that either endothelial dysfunction or eNOS phosphorylation was mediated by protein kinase C (PKC), but not by the p38 mitogen-activated protein kinase (MAPK) pathway. Consistent with this, SLO increased phosphorylation levels of PKC substrates in the aorta. In vivo study of control Wistar rats indicated that intravenous administration of SLO did not change basal blood pressure, but significantly counteracted the acetylcholine-induced decrease in blood pressure. Interestingly, plasma anti-SLO IgG levels were significantly higher in 10-to 15-week-old spontaneously hypertensive rats compared to age-matched control rats (P<0.05).These findings demonstrated that SLO causes vascular endothelial dysfunction, which is mediated by PKC-induced phosphorylation of the eNOS inhibitory site.

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“…Human serum albumin (HSA) is the most abundant protein in plasma, representing the main determinant of the oncotic pressure and of fluid distribution between body compartments [ 1 , 2 , 3 , 4 , 5 , 6 ]. Moreover, HSA is the main carrier of endogenous and exogenous ligands, including fatty acids (FAs), nucleic acids, hormones, metals, toxins, and drugs, accounts for most of the pro- and anti-oxidant capacity of plasma, and displays (pseudo-)enzymatic properties [ 4 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Furthermore, HSA plays a pivotal role in heme scavenging acting as a depot and a carrier of the macrocycle; in fact, HSA transfers the macrocycle from high- and low- density lipoproteins (i.e., HDL and LDL, respectively) to hemopexin.…”

Section: Introductionmentioning

confidence: 99%

“…HSA is a valued biomarker of many diseases, (i.e., cancer, rheumatoid arthritis, ischemia, obesity, and diabetes) [ 19 , 20 , 21 , 22 ] and finds clinical application in the treatment of several pathologies including shock, trauma, hemorrhage, acute respiratory distress syndrome, hemodialysis, acute liver failure, chronic liver disease, and hypoalbuminemia [ 4 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. In the last years, it is emerging a novel role of HSA in human innate immunity [ 9 , 12 , 30 , 31 ]. Indeed, HSA acts as a self-defense agent toward Clostridium difficile and Streptococcus pyogenes , as well as against Candida albicans infection by inactivating toxins [ 9 , 12 , 30 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Serum Albumin: A Multifaced Enzyme

Masi

Ascenzi

2021

IJMS

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106

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Human serum albumin (HSA) is the most abundant protein in plasma, contributing actively to oncotic pressure maintenance and fluid distribution between body compartments. HSA acts as the main carrier of fatty acids, recognizes metal ions, affects pharmacokinetics of many drugs, provides the metabolic modification of some ligands, renders potential toxins harmless, accounts for most of the anti-oxidant capacity of human plasma, and displays esterase, enolase, glucuronidase, and peroxidase (pseudo)-enzymatic activities. HSA-based catalysis is physiologically relevant, affecting the metabolism of endogenous and exogenous compounds including proteins, lipids, cholesterol, reactive oxygen species (ROS), and drugs. Catalytic properties of HSA are modulated by allosteric effectors, competitive inhibitors, chemical modifications, pathological conditions, and aging. HSA displays anti-oxidant properties and is critical for plasma detoxification from toxic agents and for pro-drugs activation. The enzymatic properties of HSA can be also exploited by chemical industries as a scaffold to produce libraries of catalysts with improved proficiency and stereoselectivity for water decontamination from poisonous agents and environmental contaminants, in the so called “green chemistry” field. Here, an overview of the intrinsic and metal dependent (pseudo-)enzymatic properties of HSA is reported to highlight the roles played by this multifaced protein.

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Human Serum Albumin Binds Streptolysin O (SLO) Toxin Produced by Group A Streptococcus and Inhibits Its Cytotoxic and Hemolytic Effects

Cited by 17 publications

References 57 publications

High Serum Levels of Toxin A Correlate with Disease Severity in Patients with Clostridioides difficile Infection

High Serum Levels of Toxin A Correlate with Disease Severity in Patients with Clostridioides difficile Infection

Streptococcal Exotoxin Streptolysin O Causes Vascular Endothelial Dysfunction Through PKCβ Activation

Serum Albumin: A Multifaced Enzyme

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