Magnesium therapy improves outcome in <scp><i>Streptococcus pneumoniae</i></scp> meningitis by altering pneumolysin pore formation

Hupp, Sabrina; Ribes, Sandra; Seele, Jana; Bischoff, C. A.; Förtsch, Christina; Maier, Elke; Benz, Roland; Mitchell, Tim; Nau, Roland; Iliev, Alexandar

doi:10.1111/bph.14027

Cited by 9 publications

(14 citation statements)

References 66 publications

(88 reference statements)

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“…The mechanisms involved in PLY-mediated pore formation have recently been described elsewhere [ 18 , 50 ]. Briefly, binding of CDCs to target cells involves generic mechanisms, which are critically dependent on the interaction of the common hydrophobic attachment region of domain 4 of the toxins with cholesterol head groups of the eukaryotic cell membrane [ 1 ].…”

Section: Structure and Biological Activities Of Pneumolysinmentioning

confidence: 99%

“…Hupp et al recently described the beneficial effects of magnesium chloride (MgCl 2 ), administered intraperitoneally at a therapeutically-relevant dose of 500 mg/kg body weight, in protecting young rats against the neurotoxic/neuroinflammatory effects of intracerebral injection of recombinant PLY, as well as mice, following experimental infection with strain D39 of the pneumococcus [ 50 ]. In the shorter duration experiments with PLY, MgCl 2 was administered as a single dose either before, or after the toxin, while in the murine experimental pneumococcal meningitis model the divalent cation was administered as three doses at 12-hourly intervals, the first at 30 min before induction of infection [ 50 ]. In the PLY experimental system, administration of MgCl 2 was accompanied by significant attenuation of cerebral edema, and with decreased synaptic loss and increased survival in the murine model of experimental meningitis [ 50 ].…”

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

“…In the shorter duration experiments with PLY, MgCl 2 was administered as a single dose either before, or after the toxin, while in the murine experimental pneumococcal meningitis model the divalent cation was administered as three doses at 12-hourly intervals, the first at 30 min before induction of infection [ 50 ]. In the PLY experimental system, administration of MgCl 2 was accompanied by significant attenuation of cerebral edema, and with decreased synaptic loss and increased survival in the murine model of experimental meningitis [ 50 ]. Mechanistic studies with the purified toxin and isolated glial cells in vitro demonstrated that the protective effects of MgCl 2 were not attributable to interference with the membrane-binding activity of the toxin, or with the conductance of PLY pores, but were seemingly related to delayed pore formation [ 50 ].…”

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

“…In the PLY experimental system, administration of MgCl 2 was accompanied by significant attenuation of cerebral edema, and with decreased synaptic loss and increased survival in the murine model of experimental meningitis [ 50 ]. Mechanistic studies with the purified toxin and isolated glial cells in vitro demonstrated that the protective effects of MgCl 2 were not attributable to interference with the membrane-binding activity of the toxin, or with the conductance of PLY pores, but were seemingly related to delayed pore formation [ 50 ]. Possible alternative or interactive mechanisms include competitive interference with PLY-mediated Ca 2+ influx and/or uptake of Ca 2+ via endogenous Ca 2+ channels [ 50 ].…”

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

“…Given the safety of Mg 2+ and its current therapeutic application in several clinical settings of non-infective origin, the authors propose that the findings of their “meningitis model identifies magnesium as a promising candidate for adjunctive treatment of pneumococcal meningitis together with antibiotic therapy” [ 50 ]. However, the potential of Mg 2+ to protect against myocardial injury in the settings of experimental and clinical IPD remains to be established.…”

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

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Multifaceted Role of Pneumolysin in the Pathogenesis of Myocardial Injury in Community-Acquired Pneumonia

Anderson

Nel

Feldman

2018

IJMS

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Pneumolysin (PLY), a member of the family of Gram-positive bacterial, cholesterol-dependent, β-barrel pore-forming cytolysins, is the major protein virulence factor of the dangerous respiratory pathogen, Streptococcus pneumoniae (pneumococcus). PLY plays a major role in the pathogenesis of community-acquired pneumonia (CAP), promoting colonization and invasion of the upper and lower respiratory tracts respectively, as well as extra-pulmonary dissemination of the pneumococcus. Notwithstanding its role in causing acute lung injury in severe CAP, PLY has also been implicated in the development of potentially fatal acute and delayed-onset cardiovascular events, which are now recognized as being fairly common complications of this condition. This review is focused firstly on updating mechanisms involved in the immunopathogenesis of PLY-mediated myocardial damage, specifically the direct cardiotoxic and immunosuppressive activities, as well as the indirect pro-inflammatory/pro-thrombotic activities of the toxin. Secondly, on PLY-targeted therapeutic strategies including, among others, macrolide antibiotics, natural product antagonists, cholesterol-containing liposomes, and fully humanized monoclonal antibodies, as well as on vaccine-based preventive strategies. These sections are preceded by overviews of CAP in general, the role of the pneumococcus as the causative pathogen, the occurrence and types of CAP-associated cardiac complication, and the structure and biological activities of PLY.

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Section: Structure and Biological Activities Of Pneumolysinmentioning

confidence: 99%

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

See 3 more Smart Citations

Multifaceted Role of Pneumolysin in the Pathogenesis of Myocardial Injury in Community-Acquired Pneumonia

Anderson

Nel

Feldman

2018

IJMS

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HIF-1α is involved in blood–brain barrier dysfunction and paracellular migration of bacteria in pneumococcal meningitis

et al. 2020

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Bacterial meningitis is a deadly disease most commonly caused by Streptococcus pneumoniae, leading to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer of S. pneumoniae from blood to the brain across the blood-cerebrospinal fluid barrier or the blood-brain barrier (BBB). The underlying mechanisms are still poorly understood. Current treatment strategies include adjuvant dexamethasone for inflammation and cerebral edema, followed by antibiotics. The success of dexamethasone is however inconclusive, necessitating new therapies for controlling edema, the primary reason for neurological complications. Since we have previously shown a general activation of hypoxia inducible factor (HIF-1α) in bacterial infections, we hypothesized that HIF-1α, via induction of vascular endothelial growth factor (VEGF) is involved in transmigration of pathogens across the BBB. In human, murine meningitis brain samples, HIF-1α activation was observed by immunohistochemistry. S. pneumoniae infection in brain endothelial cells (EC) resulted in in vitro upregulation of HIF-1α/VEGF (Western blotting/qRT-PCR) associated with increased paracellular permeability (fluorometry, impedance measurements). This was supported by bacterial localization at cell-cell junctions in vitro and in vivo in brain ECs from mouse and humans (confocal, super-resolution, electron microscopy, live-cell imaging). Hematogenously infected mice showed increased permeability, S. pneumoniae deposition in the brain, along with upregulation of genes in the HIF-1α/VEGF pathway (RNA sequencing of brain microvessels). Inhibition of HIF-1α with echinomycin, siRNA in bEnd5 cells or using primary brain ECs from HIF-1α knockout mice revealed reduced endothelial permeability and transmigration of S. pneumoniae. Therapeutic rescue using the HIF-1α inhibitor echinomycin resulted in increased survival and improvement of BBB function in S. pneumoniae-infected mice. We thus demonstrate paracellular migration of bacteria across BBB and a critical role for HIF-1α/VEGF therein and hence propose targeting this pathway to prevent BBB dysfunction and ensuing brain damage in infections.

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Maternal and neonatal outcomes following magnesium sulfate in the setting of chorioamnionitis: a meta-analysis

Pergialiotis,

Sapantzoglou,

Rodolaki

et al. 2023

Arch Gynecol Obstet

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Purpose Magnesium sulfate (MgSO4) has been widely used in obstetrics as a mean to help decrease maternal and neonatal morbidity in various antenatal pathology. As a factor, it seems to regulate immunity and can, thus, predispose to infectious morbidity. To date, it remains unknown if its administration can increase the risk of chorioamnionitis. In the present meta-analysis, we sought to accumulate the available evidence. Methods We systematically searched Medline, Scopus, Clinicaltrials.gov, EMBASE, Cochrane Central Register of Controlled Trials CENTRAL, and Google Scholar databases in our primary search along with the reference lists of electronically retrieved full-text papers. Results Eight studies were included that investigated the incidence of chorioamnionitis among parturient that received MgSO4 and control patients. Magnesium sulfate was administered in 3229 women and 3330 women served as controls as they did not receive MgSO4. The meta-analysis of data revealed that there was no association between the administration of magnesium sulfate and the incidence of chorioamnionitis (OR 0.98, 95% CI 0.73, 1.32). Rucker’s analysis revealed that small studies did not significantly influence the statistical significance of this finding (OR 1.12, 95% CI 0.82, 1.53). Trial sequential analysis revealed that the required number to safely interpret the primary outcome was not reached. Two studies evaluated the impact of MgSO4 in neonates delivered in the setting of chorioamnionitis. Neither of these indicated the presence of a beneficial effect in neonatal morbidity, including the risk of cerebral palsy, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, stillbirth, or neonatal death. Conclusion Current evidence indicates that magnesium sulfate is not associated with an increased risk of maternal chorioamnionitis. However, it should be noted that its effect on neonatal outcomes of offspring born in the setting of chorioamnionitis might be subtle if any, although the available evidence is very limited.

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Magnesium therapy improves outcome in Streptococcus pneumoniae meningitis by altering pneumolysin pore formation

Cited by 9 publications

References 66 publications

Multifaceted Role of Pneumolysin in the Pathogenesis of Myocardial Injury in Community-Acquired Pneumonia

Multifaceted Role of Pneumolysin in the Pathogenesis of Myocardial Injury in Community-Acquired Pneumonia

HIF-1α is involved in blood–brain barrier dysfunction and paracellular migration of bacteria in pneumococcal meningitis

Maternal and neonatal outcomes following magnesium sulfate in the setting of chorioamnionitis: a meta-analysis

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