As part of a public health behavior change and communication strategy related to the identification of a novel ebolavirus in bats in Sierra Leone in 2016, a consortium of experts launched an effort to create a widely accessible resource for community awareness and education on reducing disease risk. The resulting picture book, Living Safely With Bats, includes technical content developed by a consortium of experts in public health, animal health, conservation, bats, and disease ecology from 30 countries. The book has now been adapted, translated, and used in more than 20 countries in Africa and Asia. We review the processes used to integrate feedback from local stakeholders and multidisciplinary experts. We also provide recommendations for One Health and other practitioners who choose to pursue the development and evaluation of this or similar zoonotic disease risk mitigation tools.
Ebola virus is notorious for causing severe and even deadly haemorrhagic fever in infected humans and non-human primates. The high fatality rate of Ebola virus disease (EVD) has highlighted the need for effective diagnosis and treatment. Two monoclonal antibodies (mAbs) have been approved by USFDA for treatment of EVD. Virus surface glycoprotein is the common target for diagnostic and therapy including vaccines. Even so, VP35, a viral RNA polymerase cofactor and interferon inhibitor could be a potential target to curb EVD. The present work describes the isolation of three mAb clones from a phage-displayed human naïve scFv library against recombinant VP35. The clones showed binding against rVP35 in vitro and inhibition of VP35 in luciferase reporter gene assay. Structural modelling analysis was also carried out to identify the binding interactions involved in the antibody-antigen interaction model. This allows some insight into the "fitness" of the binding pocket between the paratope and target epitope which would be useful for the design of new mAbs through in silico means in the future. In conclusion, the information obtained from the 3 isolated mAbs could be potentially useful in the quest to improve VP35 targeting for therapeutic development in the future.
Tetherin, an interferon-inducible gene was first discovered to be an antiviral factor in 2008. A vast range of viruses, such as influenza A virus (IAV), dengue virus, Ebola virus, HIV, and RSV, have been reported to be susceptible to the antiviral activity of tetherin. Multiple reports have been published encompassing the role of tetherin in the IAV life cycle. To date, nine reports have been published regarding the role of tetherin in the IAV life cycle, with four reports supporting tetherin as an antiviral factor while five other reports suggesting no effect. To this end, this review summarizes the list of viruses currently known to be inhibited by tetherin and describes mechanisms used by viruses to overcome the antiviral potential of tetherin. Further, using IAV as disease model, we provide existing evidence in favor and against tetherin being considered as an antiviral candidate. Subsequent analysis of the experimental procedures across IAV-tetherin published reports revealed that the experimental setup (ie, cell lines, transfection reagents, and multiplicity of infection), strain-specific activity of NS1, and differing roles of NS1 in different cell lines may add up to the contributing factors leading to the discrepancies observed.
Ebola virus is a lipid-enveloped filamentous virus that affects human and non-human primates and consists of several types of protein: nucleoprotein, VP30, VP35, L protein, VP40, VP24, and transmembrane glycoprotein. Among the Ebola virus proteins, its matrix protein VP40 is abundantly expressed during infection and plays a number of critical roles in oligomerization, budding and egress from the host cell. VP40 exists predominantly as a monomer at the inner leaflet of the plasma membrane, and has been suggested to interact with negatively charged lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylserine (PS) via its cationic patch. The hydrophobic loop at the C-terminal domain has also been shown to be important in the interaction between the VP40 and the membrane. However, details of the molecular mechanisms underpinning their interactions are not fully understood. This study aimed at investigating the effects of mutation in the cationic patch and hydrophobic loop on the interaction between the VP40 monomer and the plasma membrane using coarse-grained molecular dynamics simulation (CGMD). Our simulations revealed that the interaction between VP40 and the plasma membrane is mediated by the cationic patch residues. This led to the clustering of PIP2 around the protein in the inner leaflet as a result of interactions between some cationic residues including R52, K127, K221, K224, K225, K256, K270, K274, K275 and K279 and PIP2 lipids via electrostatic interactions. Mutation of the cationic patch or hydrophobic loop amino acids caused the protein to bind at the inner leaflet of the plasma membrane in a different orientation, where no significant clustering of PIP2 was observed around the mutated protein. This study provides basic understanding of the interaction of the VP40 monomer and its mutants with the plasma membrane.
Ebola virus (EBOV) is one of the lethal viruses, causing more than 24 epidemic outbreaks to date. Despite having available molecular knowledge of this virus, no definite vaccine or other remedial agents have been developed yet for the management and avoidance of EBOV infections in humans. Disclosing this, the present study described an epitope-based peptide vaccine against EBOV, using a combination of B-cell and T-cell epitope predictions, followed by molecular docking and molecular dynamics simulation approach. Here, protein sequences of all glycoproteins of EBOV were collected and examined via in silico methods to determine the most immunogenic protein. From the identified antigenic protein, the peptide region ranging from 186 to 220 and the sequence HKEGAFFLY from the positions of 154-162 were considered the most potential B-cell and T-cell epitopes, correspondingly. Moreover, this peptide (HKEGAFFLY) interacted with HLA-A*32:15 with the highest binding energy and stability, and also a good conservancy of 83.85% with maximum population coverage. The results imply that the designed epitopes could manifest vigorous enduring defensive immunity against EBOV.
Ebola virus disease (EVD) is an emerging and remerging zoonosis associated with high fatality rate, mainly caused by the Zaire Ebola virus (ZEBOV) and Sudan Ebola virus (SEBOV) strains. Approximately 20 epidemics of EVD have been documented mainly in Central African countries since 1976. Currently, there are no therapeutics agents and vaccines yet approved for EVD. However, several promising therapeutics and vaccines candidates are actively undergoing various phase of clinical development. This study aims to study the EVD dynamics and evaluate the potential impacts of vaccines and other preventive measures on EVD transmission control and significance of medical intervention on outcome of the disease. An initial branch chain model of EVD dynamics was built based on data obtained from previous study. Different epidemiological scenarios for EVD with impacts of intervention were simulated using Berkeley-Madonna Version 8.3.18 software. Every reduction in the exposure rate of EBV infection by 10% produces two- to five-fold improvement in protection against EVD. Transmission control is optimum when the rate of exposure to EBV infection is reduced below 1%. Optimal control of EVD transmission can be achieved through strategic implementation of successful vaccination programme, and other preventive measures as well as rapid delivery of supportive medical care.
Lectins, carbohydrate-binding proteins, have been regarded as potential antiviral agents, as some can bind glycans on viral surface glycoproteins and inactivate their functions. However, clinical development of lectins has been stalled by the mitogenicity of many of these proteins, which is the ability to stimulate deleterious proliferation, especially of immune cells. We previously demonstrated that the mitogenic and antiviral activities of a lectin (banana lectin, BanLec) can be separated via a single amino acid mutation, histidine to threonine at position 84 (H84T), within the third Greek key. The resulting lectin, H84T BanLec, is virtually non-mitogenic but retains antiviral activity. Decreased mitogenicity was associated with disruption of pi-pi stacking between two aromatic amino acids. To examine whether we could provide further proof-of-principle of the ability to separate these two distinct lectin functions, we identified another lectin, Malaysian banana lectin (Malay BanLec), with similar structural features as BanLec, including pi-pi stacking, but with only 63% amino acid identity, and showed that it is both mitogenic and potently antiviral. We then engineered an F84T mutation expected to disrupt pi-pi stacking, analogous to H84T. As predicted, F84T Malay BanLec (F84T) was less mitogenic than wild type. However, F84T maintained strong antiviral activity and inhibited replication of HIV, Ebola, and other viruses. The F84T mutation disrupted pi-pi stacking without disrupting the overall lectin structure. These findings show that pi-pi stacking in the third Greek key is a conserved mitogenic motif in these two jacalin-related lectins BanLec and Malay BanLec, and further highlight the potential to rationally engineer antiviral lectins for therapeutic purposes.
The twenty-first century has witnessed some of the deadliest viral pandemics with far-reaching consequences. These include the Human Immunodeficiency Virus (HIV) (1981), Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) (2002), Influenza A virus subtype H1N1 (A/H1N1) (2009), Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (2012) and Ebola virus (2013) and the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) (2019-present). Age- and gender-based characterizations suggest that SARS-CoV-2 resembles SARS-CoV and MERS-CoV with regard tohigher fatality rates in males, and in the older population with comorbidities. The invasion-mechanism of SARS-CoV-2 and SARS-CoV, involves binding of its spike protein with angiotensin-converting enzyme 2 (ACE2) receptors; MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4), whereas H1N1 influenza is equipped with hemagglutinin protein. The viral infections-mediated immunomodulation, and progressive inflammatory state may affect the functions of several other organs. Although no effective commercial vaccine is available for any of the viruses, those against SARS-CoV-2 are being developed at an unprecedented speed. Until now, only Pfizer/BioNTech's vaccine has received temporary authorization from the UK Medicines and Healthcare products Regulatory Agency. Given the frequent emergence of viral pandemics in the 21st century, proper understanding of their characteristics and modes of action are essential to address the immediate and long-term health consequences.