scholarly journals The role of phosphatidylserine on the membrane in immunity and blood coagulation

2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Jiao Wang ◽  
Changxin Yu ◽  
Junyi Zhuang ◽  
Wenxin Qi ◽  
Jiawen Jiang ◽  
...  

AbstractThe negatively charged aminophospholipid, phosphatidylserine (PtdSer), is located in the inner leaflet of the plasma membrane in normal cells, and may be exposed to the outer leaflet under some immune and blood coagulation processes. Meanwhile, Ptdser exposed to apoptotic cells can be recognized and eliminated by various immune cells, whereas on the surface of activated platelets Ptdser interacts with coagulation factors prompting enhanced production of thrombin which significantly facilitates blood coagulation. In the case where PtdSer fails in exposure or mistakenly occurs, there are occurrences of certain immunological and haematological diseases, such as the Scott syndrome and Systemic lupus erythematosus. Besides, viruses (e.g., Human Immunodeficiency Virus (HIV), Ebola virus (EBOV)) can invade host cells through binding the exposed PtdSer. Most recently, the Corona Virus Disease 2019 (COVID-19) has been similarly linked to PtdSer or its receptors. Therefore, it is essential to comprehensively understand PtdSer and its functional characteristics. Therefore, this review summarizes Ptdser, its eversion mechanism; interaction mechanism, particularly with its immune receptors and coagulation factors; recognition sites; and its function in immune and blood processes. This review illustrates the potential aspects for the underlying pathogenic mechanism of PtdSer-related diseases, and the discovery of new therapeutic strategies as well.

Viruses ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 678 ◽  
Author(s):  
Qinghua Cui ◽  
Han Cheng ◽  
Rui Xiong ◽  
Gang Zhang ◽  
Ruikun Du ◽  
...  

Ebola virus is the causative agent of Ebola virus disease in humans. The lethality of Ebola virus infection is about 50%, supporting the urgent need to develop anti-Ebola drugs. Glycoprotein (GP) is the only surface protein of the Ebola virus, which is functionally critical for the virus to attach and enter the host cells, and is a promising target for anti-Ebola virus drug development. In this study, using the recombinant HIV-1/Ebola pseudovirus platform we previously established, we evaluated a small molecule library containing various quinoline compounds for anti-Ebola virus entry inhibitors. Some of the quinoline compounds specifically inhibited the entry of the Ebola virus. Among them, compound SYL1712 was the most potent Ebola virus entry inhibitor with an IC50 of ~1 μM. The binding of SYL1712 to the vial glycoprotein was computationally modeled and was predicted to interact with specific residues of GP. We used the time of the addition assay to show that compound SYL1712 blocks Ebola GP-mediated entry. Finally, consistent with being an Ebola virus entry inhibitor, compound SYL1712 inhibited infectious Ebola virus replication in tissue culture under biosafety level 4 containment, with an IC50 of 2 μM. In conclusion, we identified several related molecules with a diaryl-quinoline scaffold as potential anti-EBOV entry inhibitors, which can be further optimized for anti-Ebola drug development.


Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 35
Author(s):  
Marissa Acciani ◽  
Maria Lay ◽  
Katherine E. Havranek ◽  
Avery Duncan ◽  
Hersha Iyer ◽  
...  

Ebola virus (EBOV) interacts with cells using multiple categories of cell-surface receptors, including C-type lectins and phosphatidylserine (PS) receptors. PS receptors typically bind to apoptotic cell membrane PS and orchestrate the uptake and clearance of apoptotic bodies. Many viruses coated with PS-containing lipid envelopes, acquired during budding from host cells, can also exploit these receptors for internalization. PS is restricted to the inner leaflet of the plasma membrane in homeostatic cells, an orientation that would be unfavorable for PS receptor-mediated uptake if conserved on the viral envelope. Therefore, it is theorized that viral infection induces host-cell PS externalization to the outer leaflet during replication. Cells have several membrane scramblase enzymes that enrich outer leaflet PS when activated. Here, we investigate the role of two scramblases, TMEM16F and XKR8, as possible mediators of cellular and viral envelope surface PS levels during recombinant vesicular stomatitis virus (VSV) in which the VSV glycoprotein was replaced with the Ebola glycoprotein (rVSV/EBOV-GP) replication and EBOV virus-like particle (VLP) production. We find that rVSV/EBOV-GP and EBOV VLPs produced in XKR8 knockout cells contain two- to threefold less PS in their outer leaflets. Consequently, rVSV/EBOV-GP produced in deltaXKR8 is 70% less efficient at infecting cells through apoptotic mimicry as compared to the viruses produced by parental cells. In addition, the budding efficiency of both recombinant VSV particles and VLPs was significantly reduced in cells lacking XKR8. Our data suggest that virion surface PS acquisition requires XKR8 activity, whereas the deletion of TMEM16F did not affect EBOV-GP-mediated entry of VLP production. Unexpectedly, we observed an additional role of XKR8 in rVSV/G, rVSV/EBOV-GP, and EBOV VLP budding.


Author(s):  
Suleimanu Usaini ◽  
Tolulope Kayode-Adedeji ◽  
Olufunke Omole ◽  
Tunji Oyedepo

Researches in clinical and medical science have shown that Human Immunodeficiency Virus (HIV), Hepatitis B, and to some extent Hepatitis C viruses, constitute a major public health challenge in the Sub-Saharan Africa. This is without prejudice to the Ebola virus disease (EVD) that is more deadly than the other three put together, and had affected some countries in West Africa- Liberia, Sierra Leone and Guinea. There is little awareness and education via the mass media on some common viral infections in Nigeria like Hepatitis compared to HIV. Therefore, there is dire need for information, sensitisation and education on the viruses, means of transmission, preventive measures and also therapy. Edutainment is the fusion of education into entertainment programming which can come in form of drama, music, poetry and lots more, and it had been used as a platform to create awareness for positive reproductive health and HIV/AIDS by leading health organisations like WHO, USAID, DFID, SFH, and UNFPA. This paper therefore, examines why edutainment should be used and how it can be used to educate media audience in Nigeria on some viral infections that pose serious health risks and how they can live healthy lives.


F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1040
Author(s):  
Ade Hanna Natalia ◽  
Usman Sumo Friend Tambunan

Backgroud: Ebola virus disease (EVD) has spread to various countries in the world and has caused many deaths. Five different virus species can cause EVD, but the most virulent is Zaire ebolavirus (EBOV). The genome of EBOV includes seven genes that encode proteins playing essential roles in the virus lifecycle. Among these proteins, VP24 plays a vital role in the inhibition of the host cells’ immune system. Therefore, VP24 is a potential target for EVD therapy. In the present study, a potential inhibitor of EBOV VP24 activity was identified through pharmacophore-based drug design. Methods: This research was a in silico study, using pharmacophore based molecular docking simulation to obtain inhibitor candidates. Result: Terpenoids were used as VP24 inhibitor candidates. In particular, 55,979 terpenoids were obtained from the PubChem database. An initial screening based on the toxicity prediction test was performed with DataWarrior software: 3,353 ligands were shown to have a favorable toxicity profile, but only 1,375 among them had suitable pharmacophore features. These ligands were used for pharmacophore-based rigid and flexible molecular docking simulations with PDB ID: 4M0Q, chosen as the crystal structure of EBOV VP24. Six ligands predicted to have strong molecular interactions with EBOV VP24 underwent pharmacological property analysis through various software packages, including DataWarrior, SwissADME, admetSAR, pkCSM, and Toxtree. Conclusions: Taxumairol V was identified as the best candidate for EVD drug therapy via EBOV VP24 inhibition based on its molecular properties, predicted molecular interactions with the target molecule, and predicted pharmacological properties.


2020 ◽  
pp. 699-714
Author(s):  
Suleimanu Usaini ◽  
Tolulope Kayode-Adedeji ◽  
Olufunke Omole ◽  
Tunji Oyedepo

Researches in clinical and medical science have shown that Human Immunodeficiency Virus (HIV), Hepatitis B, and to some extent Hepatitis C viruses, constitute a major public health challenge in the Sub-Saharan Africa. This is without prejudice to the Ebola virus disease (EVD) that is more deadly than the other three put together, and had affected some countries in West Africa- Liberia, Sierra Leone and Guinea. There is little awareness and education via the mass media on some common viral infections in Nigeria like Hepatitis compared to HIV. Therefore, there is dire need for information, sensitisation and education on the viruses, means of transmission, preventive measures and also therapy. Edutainment is the fusion of education into entertainment programming which can come in form of drama, music, poetry and lots more, and it had been used as a platform to create awareness for positive reproductive health and HIV/AIDS by leading health organisations like WHO, USAID, DFID, SFH, and UNFPA. This paper therefore, examines why edutainment should be used and how it can be used to educate media audience in Nigeria on some viral infections that pose serious health risks and how they can live healthy lives.


Author(s):  
Marissa D. Acciani ◽  
Maria F. Lay-Mendoza ◽  
Katherine E. Havranek ◽  
Avery M. Duncan ◽  
Hersha Iyer ◽  
...  

AbstractEbola virus (EBOV) interacts with cells using two categories of cell surface receptors, C-type lectins and phosphatidylserine (PS) receptors. PS receptors typically bind to apoptotic cell membrane PS and orchestrate the uptake and clearance of apoptotic bodies. Many viruses coated with PS-containing lipid envelopes, acquired during budding from host cells, can also exploit these receptors for internalization. PS is restricted to the inner leaflet of the plasma membrane in homeostatic cells, an orientation that would be unfavorable for PS receptor-mediated uptake if conserved on the viral envelope. Therefore, it is theorized that viral infection induces host cell PS externalization to the outer leaflet during replication. Cells have several membrane scramblase enzymes that enrich outer leaflet PS when activated. Here, we investigate two scramblases, TMEM16F and XKR8, as possible mediators of cellular and viral envelope surface PS levels during recombinant VSV/EBOV-GP replication and EBOV virus-like particle (VLP) production. We found that rVSV/EBOV-GP and EBOV VLPs produced in XKR8 knockout cells contain decreased levels of PS in their outer leaflets. ΔXKR8-made rVSV/EBOV-GP is 70% less efficient at infecting cells through apoptotic mimicry compared to viruses made in parental cells. Our data suggest that virion surface PS acquisition requires XKR8 activity, whereas TMEM16F activity is not essential. Unexpectedly, we observed defective rVSV/G, rVSV/EBOV-GP, and EBOV VLP budding in ΔXKR8 cells, suggesting that phospholipid scrambling via XKR8 enhances both Ebola infectivity and budding efficiency. Overexpression of XKR8 dramatically increased budding activity, suggesting outer leaflet PS is required for both particle production and increased infectivity.ImportanceThe Democratic Republic of the Congo experienced its deadliest Ebola outbreak from 2018 to 2020, with 3,444 confirmed cases and 2,264 deaths (as of March 12, 2020). Owing to the extensive damage that these outbreaks have caused in Africa, as well as its future epidemic potential, Ebola virus (EBOV) ranks among the top eight priority pathogens outlined by the WHO in 2018. A comprehensive understanding of Ebola entry pathways into target cells is critical for antiviral development and outbreak control. Thus far, host-cell scramblases TMEM16F and XKR8 have each been named as the sole mediator of Ebola envelope surface phosphatidylserine (PS). We assessed the contributions of these proteins using CRISPR knockout cells and two EBOV models: rVSV/EBOV-GP and EBOV VLPs. We observed that XKR8 is required for optimal EBOV envelope PS levels, PS receptor engagement, and particle budding across all viral models, whereas TMEM16F did not play a major role.


Pathogens ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 850
Author(s):  
Sahil Jain ◽  
Svetlana F. Khaiboullina ◽  
Manoj Baranwal

Ebolaviruses, discovered in 1976, belongs to the Filoviridae family, which also includes Marburg and Lloviu viruses. They are negative-stranded RNA viruses with six known species identified to date. Ebola virus (EBOV) is a member of Zaire ebolavirus species and can cause the Ebola virus disease (EVD), an emerging zoonotic disease that results in homeostatic imbalance and multi-organ failure. There are three EBOV outbreaks documented in the last six years resulting in significant morbidity (>32,000 cases) and mortality (>13,500 deaths). The potential factors contributing to the high infectivity of this virus include multiple entry mechanisms, susceptibility of the host cells, employment of multiple immune evasion mechanisms and rapid person-to-person transmission. EBOV infection leads to cytokine storm, disseminated intravascular coagulation, host T cell apoptosis as well as cell mediated and humoral immune response. In this review, a concise recap of cell types targeted by EBOV and EVD symptoms followed by detailed run-through of host innate and adaptive immune responses, virus-driven regulation and their combined effects contributing to the disease pathogenesis has been presented. At last, the vaccine and drug development initiatives as well as challenges related to the management of infection have been discussed.


2010 ◽  
Vol 30 (S 01) ◽  
pp. S28-S31 ◽  
Author(s):  
J. Arroyo ◽  
L. Salazar-Sánchez ◽  
G. Jiménez-Cruz ◽  
P. Chaverri ◽  
E. Arrieta-Bolaños ◽  
...  

SummaryHaemophilia is the most frequent hereditary haemorrhagic illness and it is due to the deficiency of coagulation factors VIII (haemophilia A, HA) or IX (haemophilia B, HB).The prevalence of this disease varies according to the country, those having better survival rates having also higher prevalences. Specifically in Costa Rica, there are around 130 HA and 30 HB families. This study reports the prevalence and a spatial distribution analysis of both types of the disease in this country. The prevalence of haemophilia in this country is 7 cases per 100 000 men, for HA it is 6 cases per 100 000 and for HB it is 1 case per 100 000 male inhabitants. The prevalence of this disease is low when compared with other populations. This low prevalence could be due to the many patients that have died because of infection with human immunodeficiency virus during the 1980s. The prevalence of haemophilia in Costa Rica is almost one half of that present in developed countries. Nevertheless, the ratio between HA and HB follows world tendency: 5 : 1. In this study, nationwide geographical distribution maps were drawn in order to visualize the origin of severe cases and how this influences the pattern of distribution for both types of haemophilia. By means of these maps, it was possible to state that there is no association between the sites of maximum prevalence of mutated alleles and ethnicity. With this study, haemophilia prevalence distribution maps can be used to improve efforts for the establishment of hemophilia clinics or specialized health centers in those areas which hold the highest prevalences in this country. Also, this knowledge can be applied to improve treatment skills and offer the possibility of developing focused genetic counseling for these populations.


1978 ◽  
Vol 40 (02) ◽  
pp. 532-541 ◽  
Author(s):  
Anders Lagrelius ◽  
Nils-Olov Lunell ◽  
Margareta Blombäck

SummaryThe aim of the present study was to investigate the effect on blood coagulation and fibrinolysis of a natural oestrogen preparation, piperazine oestrone sulphate, prospectively in menopausal women. Scopolamine was given to the control group.The women were investigated before and during treatment with regard to factors VIII, VII, X, V, fibrinopeptide A, antithrombin III, plasminogen, rapid antiplasmin and α1-antitrypsin. There was no significant change towards hypercoagulability or decreased fibrinolysis in any group. In the oestrogen group, however, a tendency towards an increased level of plasminogen and a decreased level of antiplasmin was demonstrated. In the scopolamine group there was an unexpected fall in factors X and V and also in plasminogen and α1,-antitrypsin. A low level of some blood coagulation factors in some of the women before treatment is somewhat astonishing; none of them had any history of excessive bleeding.


1963 ◽  
Vol 10 (02) ◽  
pp. 295-308 ◽  
Author(s):  
Clarence Merskey ◽  
Herbert Wohl

Summary1. Groups of rats were fed thrombogenic diets and the effects on blood coagulation and fibrinolysis assessed.2. Animals fed a diet containing cholesterol, thiouracil and cholic acid developed high levels of coagulation factors I, II, V, VII—X, VIII, IX and X.3. Animals fed a similar diet with additional 40% beef fat developed even greater elevation of V, VII—X, VIII and X, similar elevation of factor II, and lesser (but still significant) elevation of factors I and IX. In addition marked elevation of blood platelets occurred.4. Euglobulin lysis time of the group not fed the additional fat was longer than in controls. Significant prolongation of euglobulin lysis time was not found in the group fed additional fat.5. If the increased levels of plasma fibrinogen were taken into account, it was found that a larger amount of fibrin was lysed per unit time in the euglobulin lysis test with plasma from rats fed either atherogenic diet compared with controls.6. Defective thromboplastin generation was present in both groups of rats fed an atherogenic diet. The defect was present in the serum and was not due to lack of a factor required for thromboplastin generation. An inhibitor was present in the serum which was capable of preventing the action of normal serum.7. No good correlation was found between the occurrence of changes in blood coagulation or fibrinolysis and the presence or absence of thrombosis and infarction.8. The exact cause of these anomalies remains unexplained, as does the cause of the thrombosis in these animals. Starvation per se does not account for these abnormal findings. They could not adequately be explained on the basis of “hypercoagulability” of the blood.


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