Filovirus Neutralising Antibodies: Mechanisms of Action and Therapeutic Application

Filoviruses, especially Ebola virus, cause sporadic outbreaks of viral haemorrhagic fever with very high case fatality rates in Africa. The 2013–2016 Ebola epidemic in West Africa provided large survivor cohorts spurring a large number of human studies which showed that specific neutralising antibodies played a key role in protection following a natural Ebola virus infection, as part of the overall humoral response and in conjunction with the cellular adaptive response. This review will discuss the studies in survivors and animal models which described protective neutralising antibody response. Their mechanisms of action will be detailed. Furthermore, the importance of neutralising antibodies in antibody-based therapeutics and in vaccine-induced responses will be explained, as well as the strategies to avoid immune escape from neutralising antibodies. Understanding the neutralising antibody response in the context of filoviruses is crucial to furthering our understanding of virus structure and function, in addition to improving current vaccines & antibody-based therapeutics.

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Antibody Attributes that Predict the Neutralization and Effector Function of Polyclonal Responses to SARS-CoV-2

10.1101/2021.08.06.21261710 ◽

2021 ◽

Author(s):

Harini Natarajan ◽

Shiwei Xu ◽

Andrew R. Crowley ◽

Ssavannah E. Butler ◽

Joshua A. Weiner ◽

...

Keyword(s):

Antibody Response ◽

Natural Infection ◽

Humoral Response ◽

Mechanisms Of Action ◽

Significant Protection ◽

Neutralization Activity ◽

Effector Functions ◽

Antiviral Antibody ◽

Response Profiles ◽

Complement Deposition

While antibodies provide significant protection from SARS-CoV-2 infection and disease sequelae, the specific attributes of the humoral response that contribute to immunity are incompletely defined. In this study, we employ machine learning to relate characteristics of the polyclonal antibody response raised by natural infection to diverse antibody effector functions and neutralization potency with the goal of generating both accurate predictions of each activity based on antibody response profiles as well as insights into antibody mechanisms of action. To this end, antibody-mediated phagocytosis, cytotoxicity, complement deposition, and neutralization were accurately predicted from biophysical antibody profiles in both discovery and validation cohorts. These predictive models identified SARS-CoV-2-specific IgM as a key predictor of neutralization activity whose mechanistic relevance was supported experimentally by depletion. Validated models of how different aspects of the humoral response relate to antiviral antibody activities suggest desirable attributes to recapitulate by vaccination or other antibody-based interventions.

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Breadth and function of antibody response to acute SARS-CoV-2 infection in humans

10.1101/2020.08.28.267526 ◽

2020 ◽

Cited By ~ 5

Author(s):

Kuan-Ying A. Huang ◽

Tiong Kit Tan ◽

Ting-Hua Chen ◽

Chung-Guei Huang ◽

Ruth Harvey ◽

...

Keyword(s):

Monoclonal Antibodies ◽

B Cells ◽

Antibody Response ◽

Somatic Mutations ◽

Therapeutic Agents ◽

Memory B Cells ◽

Wild Type ◽

Neutralising Antibodies ◽

And Function ◽

Humoral Responses

AbstractSerological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral plasmablast response. An average of 13.7% and 13.0% of plasmablast-derived MAbs were reactive with virus spike glycoprotein or nucleocapsid, respectively. A subset of anti-spike (10 of 32) and over half of anti-nucleocapsid (19 of 35) antibodies cross-reacted with other betacoronaviruses tested and harboured extensive somatic mutations, indicative of an expansion of memory B cells upon SARS-CoV-2 infection. Fourteen of 32 anti-spike MAbs, including five anti-RBD, three anti-non-RBD S1 and six anti-S2, neutralised wild-type SARS-CoV-2 in independent assays. Anti-RBD MAbs were further grouped into four cross-inhibiting clusters, of which six antibodies from three separate clusters blocked the binding of RBD to ACE2 and five were neutralising. All ACE2-blocking anti-RBD antibodies were isolated from two patients with prolonged fever, which is compatible with substantial ACE2-blocking response in their sera. At last, the identification of non-competing pairs of neutralising antibodies would offer potential templates for the development of prophylactic and therapeutic agents against SARS-CoV-2.

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Breadth and function of antibody response to acute SARS-CoV-2 infection in humans

PLoS Pathogens ◽

10.1371/journal.ppat.1009352 ◽

2021 ◽

Vol 17 (2) ◽

pp. e1009352 ◽

Cited By ~ 1

Author(s):

Kuan-Ying A. Huang ◽

Tiong Kit Tan ◽

Ting-Hua Chen ◽

Chung-Guei Huang ◽

Ruth Harvey ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Antibody Response ◽

Somatic Mutations ◽

Therapeutic Agents ◽

Memory B Cells ◽

Receptor Binding Domain ◽

Wild Type ◽

Neutralising Antibodies ◽

And Function ◽

Humoral Responses

Serological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral plasmablast response. An average of 13.7% and 13.0% of plasmablast-derived MAbs were reactive with virus spike glycoprotein or nucleocapsid, respectively. A subset of anti-spike (10 of 32) and over half of anti-nucleocapsid (19 of 35) antibodies cross-reacted with other betacoronaviruses tested and harboured extensive somatic mutations, indicative of an expansion of memory B cells upon SARS-CoV-2 infection. Fourteen of 32 anti-spike MAbs, including five anti-receptor-binding domain (RBD), three anti-non-RBD S1 and six anti-S2, neutralised wild-type SARS-CoV-2 in independent assays. Anti-RBD MAbs were further grouped into four cross-inhibiting clusters, of which six antibodies from three separate clusters blocked the binding of RBD to ACE2 and five were neutralising. All ACE2-blocking anti-RBD antibodies were isolated from two recovered patients with prolonged fever, which is compatible with substantial ACE2-blocking response in their sera. At last, the identification of non-competing pairs of neutralising antibodies would offer potential templates for the development of prophylactic and therapeutic agents against SARS-CoV-2.

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A Novel MEMS Based Immunosensor for Ebola Virus Detection

Volume 7B: Fluids Engineering Systems and Technologies ◽

10.1115/imece2013-66025 ◽

2013 ◽

Cited By ~ 3

Author(s):

Adarsh Venkataraman Ganesan

Keyword(s):

Contact Time ◽

Ebola Virus ◽

Point Of Care ◽

Virus Detection ◽

Case Fatality ◽

Comsol Multiphysics ◽

Health Issues ◽

Immunofluorescence Method ◽

Viral Haemorrhagic Fever ◽

Micro Cantilever

According to WHO, “The Ebola virus can cause several viral haemorrhagic fever (VHF) outbreaks in humans with a case fatality rate of up to 90%.” On top of these physical health issues, the Ebola virus infected patients are also subjected to many psychological problems. Recently, the ebola virus had its outbreak in Uganda on May 2011. In such places, the resources are scarce and the access to hospitals is limited. Hence, there is a need for point-of-care device for the diagnosis of Ebola virus. Currently, an expensive Immunofluorescence method is used to address this need. In this paper, the authors present the design of a robust, reliable and inexpensive microfluidic patch that is capable of detecting Ebola Virus from a fingerprick sample of whole blood. The fluidic model of the device is analyzed in COMSOL Multiphysics. The analyses show that for a contact time of 1s, approximately 5.4 μL of blood can be drawn. Further, the designed micro-cantilever was analyzed and found to effectively produce 0.23557 μV for every 10 ng of the Ebola virus present.

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Progress on the Mechanism for Aspirin’s Anti-tumor Effects

Current Drug Targets ◽

10.2174/1389450121999201013152931 ◽

2020 ◽

Vol 22 (1) ◽

pp. 105-111

Author(s):

Lin Zheng ◽

Weibiao Lv ◽

Yuanqing Zhou ◽

Xu Lin ◽

Jie Yao

Keyword(s):

Platelet Aggregation ◽

Energy Metabolism ◽

Side Effects ◽

Energy Production ◽

Immune Escape ◽

Inflammatory Responses ◽

Mechanisms Of Action ◽

Proliferation And Metastasis ◽

Review Current ◽

Granule Release

: Since its discovery more than 100 years ago, aspirin has been widely used for its antipyretic, analgesic, anti-inflammatory, and anti-rheumatic activities. In addition to these applications, it is increasingly becoming clear that the drug also has great potential in the field of cancer. Here, we briefly review current insights of aspirin’s anti-tumor effects. These are multiple and vary from inhibiting the major cellular mTOR pathways, acting as a calorie-restricted mimetic by inhibition of energy production, suppressing platelet aggregation and granule release, inhibiting immune escape of tumor cells, to decreasing inflammatory responses. We consider these five mechanisms of action the most significant of aspirin’s anti-tumor effects, whereby the anti-tumor effect may ultimately stem from its inhibition of energy metabolism, platelet function, and inflammatory response. As such, aspirin can play an important role to reduce the occurrence, proliferation, and metastasis of various types of tumors. However, most of the collected data are still based on epidemiological investi-gations. More direct and effective evidence is needed, and the side effects of aspirin intake need to be solved before this drug can be widely applied in cancer treatment.

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JOINT ESTIMATION OF THE TRANSMISSIBILITY AND SEVERITY OF EBOLA VIRUS DISEASE IN REAL TIME

Journal of Biological System ◽

10.1142/s0218339017400022 ◽

2017 ◽

Vol 25 (04) ◽

pp. 587-603 ◽

Cited By ~ 2

Author(s):

YUSUKE ASAI ◽

HIROSHI NISHIURA

Keyword(s):

Real Time ◽

Ebola Virus ◽

Virus Disease ◽

Critical Role ◽

Estimation Method ◽

Case Fatality ◽

Ascertainment Bias ◽

Joint Estimation ◽

Ebola Virus Disease ◽

Strong Impact

The effective reproduction number [Formula: see text], the average number of secondary cases that are generated by a single primary case at calendar time [Formula: see text], plays a critical role in interpreting the temporal transmission dynamics of an infectious disease epidemic, while the case fatality risk (CFR) is an indispensable measure of the severity of disease. In many instances, [Formula: see text] is estimated using the reported number of cases (i.e., the incidence data), but such report often does not arrive on time, and moreover, the rate of diagnosis could change as a function of time, especially if we handle diseases that involve substantial number of asymptomatic and mild infections and large outbreaks that go beyond the local capacity of reporting. In addition, CFR is well known to be prone to ascertainment bias, often erroneously overestimated. In this paper, we propose a joint estimation method of [Formula: see text] and CFR of Ebola virus disease (EVD), analyzing the early epidemic data of EVD from March to October 2014 and addressing the ascertainment bias in real time. To assess the reliability of the proposed method, coverage probabilities were computed. When ascertainment effort plays a role in interpreting the epidemiological dynamics, it is useful to analyze not only reported (confirmed or suspected) cases, but also the temporal distribution of deceased individuals to avoid any strong impact of time dependent changes in diagnosis and reporting.

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Antibody response to common viruses and human leukocyte antigen-DRB1 in pediatric multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458512469693 ◽

2012 ◽

Vol 19 (7) ◽

pp. 891-895 ◽

Cited By ~ 20

Author(s):

Emmanuelle Waubant ◽

Ellen M Mowry ◽

Lauren Krupp ◽

Tanuja Chitnis ◽

E Ann Yeh ◽

...

Keyword(s):

Multiple Sclerosis ◽

Antibody Response ◽

Human Leukocyte Antigen ◽

Human Leukocyte ◽

Humoral Response ◽

Nuclear Antigen ◽

Leukocyte Antigen ◽

Epstein Barr ◽

Humoral Responses ◽

Hsv 1

Background: As remote infections with common herpes viruses are associated with modulation of the risk of multiple sclerosis (MS), we hypothesized that antibody concentrations against these viruses may further modify risk. As many common viruses are first encountered during childhood, pediatric MS offer a unique opportunity to investigate more closely their influence on susceptibility. Our aim was to determine if MS patients who were positive for these viruses had higher levels of antibodies to these viruses. We also assessed whether human leukocyte antigen (HLA)-DRB1*1501 genotype influenced viral antibody levels. Methods: Antibody response levels toward Epstein Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV)-1, and HLA-DRB1*1501 status were determined in pediatric MS patients ( n=189) and controls ( n=38). Multivariate analyses were used, adjusted for age, gender, race, ethnicity and use of disease-modifying therapies. Results: The antibody concentrations against EBV (Epstein-Barr nuclear antigen 1 (EBNA-1), viral capsid antigen (VCA) and early antigen (EA)), CMV and HSV-1 were similar between pediatric MS patients and controls positive for seroconversion against the virus of interest. EBNA-1 humoral responses were higher in HLA-DRB1 positive individuals ( p=0.005) whereas other viral humoral responses were similar in HLA-DRB1 positive and negative individuals. Conclusion: Among those positive for EBNA-1, MS patients did not have higher levels of antibody response to EBNA-1: however, titers for EBNA-1 were higher in those who were HLA-DRB1 positive. This suggests that genotype might influence the humoral response to EBV. Whether other genotypes influence antibody response to other viruses remains to be determined.

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15-Lipoxygenase-2 Deficiency Induces a Dysfunction in Macrophages That Can Be Restored by Salidroside

10.21203/rs.3.rs-144514/v1 ◽

2021 ◽

Author(s):

Rong Huang Huang ◽

Tingting Li Li ◽

Xi Yong Yong ◽

Huling Wen Wen ◽

Xing Zhou Zhou ◽

...

Keyword(s):

Natural Product ◽

Signaling Pathway ◽

Therapeutic Strategy ◽

Caspase 3 ◽

Mechanisms Of Action ◽

Rna Seq ◽

Immunological Function ◽

Tnf Α ◽

And Function ◽

Genetic Strategies

Abstract 15-Lipoxygenase-2(15-LOX-2) is thought to regulate inflammation and immunological function however, its mechanisms of action are still unclear. Furthermore, it has been reported that salidroside has anti inflammatory properties , but its role in macrophage function has not been understood yet In this study, we aimed to determine how 15-LOX-2 expression level s affect the function of macrophages and the effect of salidroside on 15-LOX-2 deficient macrophages We used multiple functional genetic strategies to determine 15-LOX-2 function in macrophages. 15-LOX-2 deficiency promotes phagocytosis and proliferation of macrophages and impairs their apoptosis Mechanistically, t he expression levels of cyclophilinB (CypB) were upregulated in 15-LOX-2 deficient Ana 1 macrophages, whereas those of caspase 3 were down regulated. Furthermore, RNA-seq analysis showed that inflammation, complement, and TNF-α signaling pathway s were all activated in 15-LOX-2 deficient Ana 1 macrophages. Treatment of 15-LOX-2 deficient macrophages with salidroside, a natural product derived from Rhodiola species, effectively reversed the effects of 15-LOX-2 deficiency on caspase 3 and CypB levels, as well as on apoptosis and proliferation. In conclusion, our study shows that there is a newly identified link between 15-LOX-2 deficiency and salidroside in regulating macrophage survival, proliferation, and function. Salidroside may be a promising therapeutic strategy for treating inflammation related diseases resulting from 15-LOX-2 deficiency.

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