scholarly journals Small Pore-Forming Toxins Different Membrane Area Binding and Ca2+ Permeability of Pores Determine Cellular Resistance of Monocytic Cells

Toxins ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 126
Author(s):  
Yu Larpin ◽  
Hervé Besançon ◽  
Victoriia S. Babiychuk ◽  
Eduard B. Babiychuk ◽  
René Köffel
Keyword(s):  
Host Cell ◽  
Immune Cell ◽  
Pore Channel ◽  
U937 Cells ◽  
Membrane Repair ◽  
Channel Diameter ◽  
Cellular Resistance ◽  
Membrane Area ◽  
Small Pore ◽  
Repair Mechanisms

Pore-forming toxins (PFTs) form multimeric trans-membrane pores in cell membranes that differ in pore channel diameter (PCD). Cellular resistance to large PFTs (>20 nm PCD) was shown to rely on Ca2+ influx activated membrane repair mechanisms. Small PFTs (<2 nm PCD) were shown to exhibit a high cytotoxic activity, but host cell response and membrane repair mechanisms are less well studied. We used monocytic immune cell lines to investigate the cellular resistance and host membrane repair mechanisms to small PFTs lysenin (Eisenia fetida) and aerolysin (Aeromonas hydrophila). Lysenin, but not aerolysin, is shown to induce Ca2+ influx from the extracellular space and to activate Ca2+ dependent membrane repair mechanisms. Moreover, lysenin binds to U937 cells with higher efficiency as compared to THP-1 cells, which is in line with a high sensitivity of U937 cells to lysenin. In contrast, aerolysin equally binds to U937 or THP-1 cells, but in different plasma membrane areas. Increased aerolysin induced cell death of U937 cells, as compared to THP-1 cells, is suggested to be a consequence of cap-like aerolysin binding. We conclude that host cell resistance to small PFTs attack comprises binding efficiency, pore localization, and capability to induce Ca2+ dependent membrane repair mechanisms.

scholarly journals Plasma membrane integrity in health and disease: significance and therapeutic potential

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Catarina Dias ◽  
Jesper Nylandsted
Keyword(s):  
Plasma Membrane ◽  
Therapeutic Potential ◽  
Calcium Influx ◽  
Membrane Integrity ◽  
Cell Types ◽  
Physical Parameters ◽  
Membrane Repair ◽  
Plasma Membrane Integrity ◽  
Repair Mechanisms ◽  
And Function

AbstractMaintenance of plasma membrane integrity is essential for normal cell viability and function. Thus, robust membrane repair mechanisms have evolved to counteract the eminent threat of a torn plasma membrane. Different repair mechanisms and the bio-physical parameters required for efficient repair are now emerging from different research groups. However, less is known about when these mechanisms come into play. This review focuses on the existence of membrane disruptions and repair mechanisms in both physiological and pathological conditions, and across multiple cell types, albeit to different degrees. Fundamentally, irrespective of the source of membrane disruption, aberrant calcium influx is the common stimulus that activates the membrane repair response. Inadequate repair responses can tip the balance between physiology and pathology, highlighting the significance of plasma membrane integrity. For example, an over-activated repair response can promote cancer invasion, while the inability to efficiently repair membrane can drive neurodegeneration and muscular dystrophies. The interdisciplinary view explored here emphasises the widespread potential of targeting plasma membrane repair mechanisms for therapeutic purposes.

scholarly journals The Protozoan Parasite Toxoplasma gondii Selectively Reprograms the Host Cell Translatome

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Louis-Philippe Leroux ◽  
Julie Lorent ◽  
Tyson E. Graber ◽  
Visnu Chaparro ◽  
Laia Masvidal ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cell ◽  
Cell Activation ◽  
Immune Cell ◽  
Mrna Translation ◽  
Protozoan Parasite ◽  
Translational Efficiency ◽  
Type I ◽  
Content Type ◽  
Infection Inhibition

ABSTRACT The intracellular parasite Toxoplasma gondii promotes infection by targeting multiple host cell processes; however, whether it modulates mRNA translation is currently unknown. Here, we show that infection of primary murine macrophages with type I or II T. gondii strains causes a profound perturbation of the host cell translatome. Notably, translation of transcripts encoding proteins involved in metabolic activity and components of the translation machinery was activated upon infection. In contrast, the translational efficiency of mRNAs related to immune cell activation and cytoskeleton/cytoplasm organization was largely suppressed. Mechanistically, T. gondii bolstered mechanistic target of rapamycin (mTOR) signaling to selectively activate the translation of mTOR-sensitive mRNAs, including those with a 5′-terminal oligopyrimidine (5′ TOP) motif and those encoding mitochondrion-related proteins. Consistent with parasite modulation of host mTOR-sensitive translation to promote infection, inhibition of mTOR activity suppressed T. gondii replication. Thus, selective reprogramming of host mRNA translation represents an important subversion strategy during T. gondii infection.

Nanosponges intercept coronavirus infection

2020 ◽  
Vol 12 (550) ◽  
pp. eabd3078
Author(s):  
Su Xinyi
Keyword(s):  
Cell Culture ◽  
Host Cell ◽  
Cell Membranes ◽  
Immune Cell ◽  
Human Lung ◽  
Cell Infection ◽  
Coronavirus Infection

Nanoparticles cloaked in human lung and immune cell membranes act as decoys to neutralize SARS-CoV-2 in cell culture, preventing host cell infection.

scholarly journals Membrane Repair: Mechanisms and Pathophysiology

2015 ◽  
Vol 95 (4) ◽  
pp. 1205-1240 ◽  
Author(s):  
Sandra T. Cooper ◽  
Paul L. McNeil
Keyword(s):  
Molecular Mechanisms ◽  
Eukaryotic Cells ◽  
Membrane Repair ◽  
Membrane Pore ◽  
Rapid Repair ◽  
Repair Mechanisms ◽  
Molecular Machinery ◽  
Repair Pathways ◽  
Different Tissues ◽  
Ischemic Stress

Eukaryotic cells have been confronted throughout their evolution with potentially lethal plasma membrane injuries, including those caused by osmotic stress, by infection from bacterial toxins and parasites, and by mechanical and ischemic stress. The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. Calcium has been identified as the key trigger to activate an effective membrane repair response that utilizes exocytosis and endocytosis to repair a membrane tear, or remove a membrane pore. We here review what is known about the cellular and molecular mechanisms of membrane repair, with particular emphasis on the relevance of repair as it relates to disease pathologies. Collective evidence reveals membrane repair employs primitive yet robust molecular machinery, such as vesicle fusion and contractile rings, processes evolutionarily honed for simplicity and success. Yet to be fully understood is whether core membrane repair machinery exists in all cells, or whether evolutionary adaptation has resulted in multiple compensatory repair pathways that specialize in different tissues and cells within our body.

scholarly journals Actin Cytoskeletal Dynamics in Single-Cell Wound Repair

2021 ◽  
Vol 22 (19) ◽  
pp. 10886
Author(s):  
Malene Laage Ebstrup ◽  
Catarina Dias ◽  
Anne Sofie Busk Heitmann ◽  
Stine Lauritzen Sønder ◽  
Jesper Nylandsted
Keyword(s):  
Plasma Membrane ◽  
Actin Cytoskeleton ◽  
Single Cell ◽  
Wound Repair ◽  
Membrane Integrity ◽  
Limited Attention ◽  
Membrane Repair ◽  
Cortical Actin ◽  
Comprehensive Overview ◽  
Repair Mechanisms

The plasma membrane protects the eukaryotic cell from its surroundings and is essential for cell viability; thus, it is crucial that membrane disruptions are repaired quickly to prevent immediate dyshomeostasis and cell death. Accordingly, cells have developed efficient repair mechanisms to rapidly reseal ruptures and reestablish membrane integrity. The cortical actin cytoskeleton plays an instrumental role in both plasma membrane resealing and restructuring in response to damage. Actin directly aids membrane repair or indirectly assists auxiliary repair mechanisms. Studies investigating single-cell wound repair have often focused on the recruitment and activation of specialized repair machinery, despite the undeniable need for rapid and dynamic cortical actin modulation; thus, the role of the cortical actin cytoskeleton during wound repair has received limited attention. This review aims to provide a comprehensive overview of membrane repair mechanisms directly or indirectly involving cortical actin cytoskeletal remodeling.

scholarly journals Leishmania amazonensis hijacks host cell lysosomes involved in plasma membrane repair to induce invasion in fibroblasts

2019 ◽  
Vol 132 (6) ◽  
pp. jcs226183 ◽  
Author(s):  
Victor Soares Cavalcante-Costa ◽  
Mariana Costa-Reginaldo ◽  
Thamires Queiroz-Oliveira ◽  
Anny C. S. Oliveira ◽  
Natália Fernanda Couto ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Host Cell ◽  
Leishmania Amazonensis ◽  
Membrane Repair ◽  
Plasma Membrane Repair

Phase I study of a novel S1P inhibitor, NOX66, in combination with radiotherapy in patients with metastatic castration-resistant prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5533-5533
Author(s):  
Paul L. de Souza ◽  
Anne Louise Capp ◽  
Nana Chikhladze ◽  
Zaza Mezvrishvili ◽  
Marinella Messina ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Late Stage ◽  
Immune Cell ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Repair Mechanisms ◽  
Psa Response ◽  
Grade 3 ◽  
Expansion Cohort ◽  
New Formulation

5533 Background: NOX66 is a new formulation of the small molecule, idronoxil. The primary mechanism of action of idronoxil stems from its binding to the transmembrane enzyme ENOX2 expressed on cancer cells, resulting in reduced S1P and increased ceramide levels, thereby promoting apoptosis. Additional intracellular effects include the inhibition of DNA repair mechanisms. There is growing evidence that S1P is a promotor of tumour resistance to immune cell infiltration, highlighting NOX66’s potential to modulate the immune response against cancer. Methods: This two-part phase 1b open-label study enrolled patients with late-stage progressive mCRPC. Part 1 was a dose-escalation safety assessment of three doses of NOX66 (400 mg, n = 4; 800 mg, n = 6 and 1200 mg, n = 15) administered daily for 14 days with radiation therapy (20 Gy) delivered in 5 fractionated doses to one or more symptomatic lesion/s. Part 2 was an expansion cohort with NOX66 at 1200 mg in conjunction with radiation therapy. The primary endpoint of safety was assessed by the frequency and grade of treatment-emergent adverse events (TEAEs). At 6 weeks, 3- and 6-month follow up, treatment response was assessed radiographically by RECIST1.1 and by PSA >50% reduction. Results: 25 patients received and completed treatment. TEAEs considered related to NOX66 alone were mild (Grade 1) cases of dry mouth and oral mucositis; mild (Grade 1) fatigue was considered related to both NOX66 and radiation. None of the 21 Grade ≥3 TEAEs were considered related to NOX66. At 6 months, of the 15 evaluable patients by RECIST1.1, 9 had SD and 1 had PR and these same patients had maintained this response from 3 months. Five of the 16 PSA-evaluable patients achieved a PSA response (61-98% PSA reduction) at 6 months, which again was maintained from 3 months. Conclusions: NOX66 in combination with low-dose radiation therapy was found to be safe and well tolerated with promising signals of durable efficacy in patients with late-stage mCRPC. Responses of lesions outside the radiation field are being reviewed. Clinical trial information: NCT03307629 .

Host cell glutamine metabolism as a potential antiviral target

2021 ◽  
Vol 135 (2) ◽  
pp. 305-325
Author(s):  
Sandro Massao Hirabara ◽  
Renata Gorjao ◽  
Adriana Cristina Levada-Pires ◽  
Laureane Nunes Masi ◽  
Elaine Hatanaka ◽  
...  
Keyword(s):  
Host Cell ◽  
Immune Cell ◽  
Antiviral Drugs ◽  
Viral Envelope ◽  
Host Cells ◽  
Glutamine Metabolism ◽  
Infected Host ◽  
Potential Candidate ◽  
Cell Functions ◽  
Glutamine Transport

Abstract A virus minimally contains a nucleic acid genome packaged by a protein coat. The genome and capsid together are known as the nucleocapsid, which has an envelope containing a lipid bilayer (mainly phospholipids) originating from host cell membranes. The viral envelope has transmembrane proteins that are usually glycoproteins. The proteins in the envelope bind to host cell receptors, promoting membrane fusion and viral entry into the cell. Virus-infected host cells exhibit marked increases in glutamine utilization and metabolism. Glutamine metabolism generates ATP and precursors for the synthesis of macromolecules to assemble progeny viruses. Some compounds derived from glutamine are used in the synthesis of purines and pyrimidines. These latter compounds are precursors for the synthesis of nucleotides. Inhibitors of glutamine transport and metabolism are potential candidate antiviral drugs. Glutamine is also an essential nutrient for the functions of leukocytes (lymphocyte, macrophage, and neutrophil), including those in virus-infected patients. The increased glutamine requirement for immune cell functions occurs concomitantly with the high glutamine utilization by host cells in virus-infected patients. The development of antiviral drugs that target glutamine metabolism must then be specifically directed at virus-infected host cells to avoid negative effects on immune functions. Therefore, the aim of this review was to describe the landscape of cellular glutamine metabolism to search for potential candidates to inhibit glutamine transport or glutamine metabolism.

scholarly journals LAMP-2 absence interferes with plasma membrane repair and decreases T. cruzi host cell invasion

2017 ◽  
Vol 11 (6) ◽  
pp. e0005657 ◽  
Author(s):  
Natália Fernanda Couto ◽  
Dina Pedersane ◽  
Luisa Rezende ◽  
Patrícia P. Dias ◽  
Tayanne L. Corbani ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Host Cell ◽  
Cell Invasion ◽  
Host Cell Invasion ◽  
Membrane Repair ◽  
Plasma Membrane Repair

scholarly journals Repair of a Bacterial Small β-Barrel Toxin Pore Depends on Channel Width

mBio ◽  
2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Gisela von Hoven ◽  
Amable J. Rivas ◽  
Claudia Neukirch ◽  
Martina Meyenburg ◽  
Qianqian Qin ◽  
...  
Keyword(s):  
Vibrio Cholerae ◽  
Cellular Responses ◽  
Channel Width ◽  
Target Cells ◽  
Alpha Toxin ◽  
Membrane Repair ◽  
Critical Determinant ◽  
Membrane Pores ◽  
Transmembrane Pores ◽  
Repair Mechanisms

ABSTRACT Membrane repair emerges as an innate defense protecting target cells against bacterial pore-forming toxins. Here, we report the first paradigm of Ca2+-dependent repair following attack by a small β-pore-forming toxin, namely, plasmid-encoded phobalysin of Photobacterium damselae subsp. damselae. In striking contrast, Vibrio cholerae cytolysin, the closest ortholog of phobalysin, subverted repair. Mutational analysis uncovered a role of channel width in toxicity and repair. Thus, the replacement of serine at phobalysin´s presumed channel narrow point with the bulkier tryptophan, the corresponding residue in Vibrio cholerae cytolysin (W318), modulated Ca2+ influx, lysosomal exocytosis, and membrane repair. And yet, replacing tryptophan (W318) with serine in Vibrio cholerae cytolysin enhanced toxicity. The data reveal divergent strategies evolved by two related small β-pore-forming toxins to manipulate target cells: phobalysin leads to fulminant perturbation of ion concentrations, closely followed by Ca2+ influx-dependent membrane repair. In contrast, V. cholerae cytolysin causes insidious perturbations and escapes control by the cellular wounded membrane repair-like response. IMPORTANCE Previous studies demonstrated that large transmembrane pores, such as those formed by perforin or bacterial toxins of the cholesterol-dependent cytolysin family, trigger rapid, Ca2+ influx-dependent repair mechanisms. In contrast, recovery from attack by the small β-pore-forming Staphylococcus aureus alpha-toxin or aerolysin is slow in comparison and does not depend on extracellular Ca2+. To further elucidate the scope of Ca2+ influx-dependent repair and understand its limitations, we compared the cellular responses to phobalysin and V. cholerae cytolysin, two related small β-pore-forming toxins which create membrane pores of slightly different sizes. The data indicate that the channel width of a small β-pore-forming toxin is a critical determinant of both primary toxicity and susceptibility to Ca2+-dependent repair. IMPORTANCE Previous studies demonstrated that large transmembrane pores, such as those formed by perforin or bacterial toxins of the cholesterol-dependent cytolysin family, trigger rapid, Ca2+ influx-dependent repair mechanisms. In contrast, recovery from attack by the small β-pore-forming Staphylococcus aureus alpha-toxin or aerolysin is slow in comparison and does not depend on extracellular Ca2+. To further elucidate the scope of Ca2+ influx-dependent repair and understand its limitations, we compared the cellular responses to phobalysin and V. cholerae cytolysin, two related small β-pore-forming toxins which create membrane pores of slightly different sizes. The data indicate that the channel width of a small β-pore-forming toxin is a critical determinant of both primary toxicity and susceptibility to Ca2+-dependent repair.

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