The Induction of a Primary Anti-Protein Response in vitro: Regulatory Influence of the Particulate Carrier Bordetella pertussis

2015 ◽  
pp. 291-298 ◽  
Author(s):  
K.-U. Hartmann ◽  
A.M. Dr�ger ◽  
N. Brattig ◽  
C. Bischoff ◽  
H. St�tter
Keyword(s):  
Bordetella Pertussis ◽  
Regulatory Influence ◽  
Particulate Carrier ◽  
Protein Response

Stew in its Own Juice: Protein Homeostasis Machinery Inhibition Reduces Cell Viability in Multiple Myeloma Cell Lines

2019 ◽  
Vol 19 (2) ◽  
pp. 112-119 ◽  
Author(s):  
Mariana B. de Oliveira ◽  
Luiz F.G. Sanson ◽  
Angela I.P. Eugenio ◽  
Rebecca S.S. Barbosa-Dantas ◽  
Gisele W.B. Colleoni
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Viability ◽  
Cell Lines ◽  
Treatment Options ◽  
Compensatory Mechanism ◽  
Protein Homeostasis ◽  
Protein Response ◽  
Rpmi 8226

Introduction:Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR).Methods:We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors.Results:For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload.Conclusion:Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.

scholarly journals The Effects of Bergamot Polyphenolic Fraction, Cynara cardunculus, and Olea europea L. Extract on Doxorubicin-Induced Cardiotoxicity

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2158
Author(s):  
Jessica Maiuolo ◽  
Irene Bava ◽  
Cristina Carresi ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Apoptotic Cell ◽  
Natural Compounds ◽  
Cynara Cardunculus ◽  
Unfolded Protein ◽  
Wide Range ◽  
Vitro Model ◽  
The Unfolded Protein Response ◽  
Protein Response

Doxorubicin is an anthracycline that is commonly used as a chemotherapy drug due to its cytotoxic effects. The clinical use of doxorubicin is limited due to its known cardiotoxic effects. Treatment with anthracyclines causes heart failure in 15–17% of patients, resulting in mitochondrial dysfunction, the accumulation of reactive oxygen species, intracellular calcium dysregulation, the deterioration of the cardiomyocyte structure, and apoptotic cell death. Polyphenols have a wide range of beneficial properties, and particular importance is given to Bergamot Polyphenolic Fraction; Oleuropein, one of the main polyphenolic compounds of olive oil; and Cynara cardunculus extract. These natural compounds have particular beneficial characteristics, owing to their high polyphenol contents. Among these, their antioxidant and antoproliferative properties are the most important. The aim of this paper was to investigate the effects of these three plant derivatives using an in vitro model of cardiotoxicity induced by the treatment of rat embryonic cardiomyoblasts (H9c2) with doxorubicin. The biological mechanisms involved and the crosstalk existing between the mitochondria and the endoplasmic reticulum were examined. Bergamot Polyphenolic Fraction, Oleuropein, and Cynara cardunculus extract were able to decrease the damage induced by exposure to doxorubicin. In particular, these natural compounds were found to reduce cell mortality and oxidative damage, increase the lipid content, and decrease the concentration of calcium ions that escaped from the endoplasmic reticulum. In addition, the direct involvement of this cellular organelle was demonstrated by silencing the ATF6 arm of the Unfolded Protein Response, which was activated after treatment with doxorubicin.

In vitro innate immune cell based models to assess whole cell Bordetella pertussis vaccine quality: A proof of principle

Biologicals ◽  
2015 ◽  
Vol 43 (2) ◽  
pp. 100-109 ◽  
Author(s):  
M.E. Hoonakker ◽  
L.M. Verhagen ◽  
C.F.M. Hendriksen ◽  
C.A.C.M. van Els ◽  
R.J. Vandebriel ◽  
...  
Keyword(s):  
Pertussis Vaccine ◽  
Bordetella Pertussis ◽  
Immune Cell ◽  
Innate Immune ◽  
Innate Immune Cell ◽  
Whole Cell ◽  
Proof Of Principle

scholarly journals The intracerebral infection of mice with Bordetella pertussis

1961 ◽  
Vol 59 (2) ◽  
pp. 205-216 ◽  
Author(s):  
Jean M. Dolby ◽  
A. F. B. Standfast
Keyword(s):  
Bordetella Pertussis ◽  
Viable Count ◽  
Lethal Level ◽  
Virulent Strains ◽  
Single Organism ◽  
Striking Change ◽  
Circulating Antibodies ◽  
Intracerebral Infection

The growth of virulent strains of Bordetella pertussis in the brains of mice was studied by carrying out viable counts on mice killed at various times during the infection. The results suggested that this system conformed to the general model which postulates that the organisms causing death multiply in vivo at a rate which is constant for all doses and that death is certain to occur when the number of organisms reaches a certain constant figure.Perhaps the most important factor in this route of infection is the lodgement of the parasite in the host, for if this is accomplished a single organism grows until the lethal level is reached. There is no sublethal infection.In actively and passively protected mice, the growth of the organism is approximately the same as in unprotected controls for the first 4–5 days. At this time there is a striking change in protected animals and the viable count falls rapidly and progressively and the animals survive. At the same time the blood-brain barrier becomes permeable and circulating antibodies diffuse into the brain. In vitro, specific antisera plus complement are highly bactericidal.

scholarly journals HiPSC-Derived Hepatocyte-like Cells Can Be Used as a Model for Transcriptomics-Based Study of Chemical Toxicity

Toxics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 1
Author(s):  
Sreya Ghosh ◽  
Jonathan De Smedt ◽  
Tine Tricot ◽  
Susana Proença ◽  
Manoj Kumar ◽  
...  
Keyword(s):  
Response To Treatment ◽  
Chemical Toxicity ◽  
Hepatocellular Injury ◽  
Unfolded Protein ◽  
Toxicity Studies ◽  
Toxicity Risk ◽  
Transcriptomics Data ◽  
Induced Pluripotent ◽  
Protein Response

Traditional toxicity risk assessment approaches have until recently focussed mainly on histochemical readouts for cell death. Modern toxicology methods attempt to deduce a mechanistic understanding of pathways involved in the development of toxicity, by using transcriptomics and other big data-driven methods such as high-content screening. Here, we used a recently described optimised method to differentiate human induced pluripotent stem cells (hiPSCs) to hepatocyte-like cells (HLCs), to assess their potential to classify hepatotoxic and non-hepatotoxic chemicals and their use in mechanistic toxicity studies. The iPSC-HLCs could accurately classify chemicals causing acute hepatocellular injury, and the transcriptomics data on treated HLCs obtained by TempO-Seq technology linked the cytotoxicity to cellular stress pathways, including oxidative stress and unfolded protein response (UPR). Induction of these stress pathways in response to amiodarone, diclofenac, and ibuprofen, was demonstrated to be concentration and time dependent. The transcriptomics data on diclofenac-treated HLCs were found to be more sensitive in detecting differentially expressed genes in response to treatment, as compared to existing datasets of other diclofenac-treated in vitro hepatocyte models. Hence iPSC-HLCs generated by transcription factor overexpression and in metabolically optimised medium appear suitable for chemical toxicity detection as well as mechanistic toxicity studies.

scholarly journals Effects of Bordetella pertussis infection on human respiratory epithelium in vivo and in vitro.

1991 ◽  
Vol 59 (1) ◽  
pp. 337-345 ◽  
Author(s):  
R Wilson ◽  
R Read ◽  
M Thomas ◽  
A Rutman ◽  
K Harrison ◽  
...  
Keyword(s):  
Bordetella Pertussis ◽  
Respiratory Epithelium ◽  
Pertussis Infection

scholarly journals BordetellaAdenylate Cyclase Toxin Inhibits Monocyte-to-Macrophage Transition and Dedifferentiates Human Alveolar Macrophages into Monocyte-like Cells

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Jawid Nazir Ahmad ◽  
Jana Holubova ◽  
Oldrich Benada ◽  
Olga Kofronova ◽  
Ludek Stehlik ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Immune Evasion ◽  
Bordetella Pertussis ◽  
Alveolar Macrophages ◽  
Human Monocyte ◽  
Content Type ◽  
Macrophage Cells ◽  
Human Alveolar Macrophages ◽  
Adenylate Cyclase Toxin

ABSTRACTMonocytes arriving at the site of infection differentiate into functional effector macrophages to replenish the resident sentinel cells.Bordetella pertussis, the pertussis agent, secretes an adenylate cyclase toxin-hemolysin (CyaA) that binds myeloid phagocytes through complement receptor 3 (CD11b/CD18) and swiftly delivers its adenylyl cyclase enzyme domain into phagocytes. This ablates the bactericidal capacities of phagocytes through massive and unregulated conversion of cytosolic ATP into the key signaling molecule cAMP. We show that exposure of primary human monocytes to as low a concentration as 22.5 pM CyaA, or a low (2:1) multiplicity of infection by CyaA-producingB. pertussisbacteria, blocks macrophage colony-stimulating factor (M-CSF)-driven differentiation of monocytes. CyaA-induced cAMP signaling mediated through the activity of protein kinase A (PKA) efficiently blocked expression of macrophage markers, and the monocytes exposed to 22.5 pM CyaA failed to acquire the characteristic intracellular complexity of mature macrophage cells. Neither M-CSF-induced endoplasmic reticulum (ER) expansion nor accumulation of Golgi bodies, mitochondria, or lysosomes was observed in toxin-exposed monocytes, which remained small and poorly phagocytic and lacked pseudopodia. Exposure to 22.5 pM CyaA toxin provoked loss of macrophage marker expression onin vitrodifferentiated macrophages, as well as on primary human alveolar macrophages, which appeared to dedifferentiate into monocyte-like cells with upregulated CD14 levels. This is the first report that terminally differentiated tissue-resident macrophage cells can be dedifferentiatedin vitro. The results suggest that blocking of monocyte-to-macrophage transition and/or dedifferentiation of the sentinel cells of innate immunity through cAMP-elevating toxin action may represent a novel immune evasion strategy of bacterial pathogens.IMPORTANCEMacrophages are key sentinel cells of the immune system, and, as such, they are targeted by the toxins produced by the pertussis agentBordetella pertussis. The adenylate cyclase toxin (CyaA) mediates immune evasion ofB. pertussisby suspending the bactericidal activities of myeloid phagocytes. We reveal a novel mechanism of potential subversion of host immunity, where CyaA at very low (22 pM) concentrations could inhibit maturation of human monocyte precursors into the more phagocytic macrophage cells. Furthermore, exposure to low CyaA amounts has been shown to trigger dedifferentiation of mature primary human alveolar macrophages back into monocyte-like cells. This unprecedented capacity is likely to promote survival of the pathogen in the airways, both by preventing maturation of monocytes attracted to the site of infection into phagocytic macrophages and by dedifferentiation of the already airway-resident sentinel cells.

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