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Review Article Emerging Therapeutic Approaches to Combat the Pandemicity of the Deadly Minyahil Alebachew Woldu*1, Jimma Likisa Lenjisa2, Gobezie Temesgen Tegegne2 and Gizaw Dabessa Satessa2

1Department of pharmacology and clinical , School of pharmacy, college of health sciences, Addis Ababa University, Addis Ababa-Ethiopia 2Clinical pharmacy unit, department of pharmacy, college of and health sciences, Ambo University, Ambo-Ethiopia

ABSTRACT Background: Since the identification of Ebola Virus (EBOV) in

1976, significant filovirus research has focused on developing antiviral . However, despite promising candidates, no licensed prophylactics currently exist for preventing or treating filovirus infections. Pathogenesis: The Ebola encodes only seven genes, which mediate the entry, replication, and egress of the virus from the host cell. have been identified as a reservoir for Ebola but it remains unclear if transmission to an end host involves intermediate hosts. Diagnosis: Diagnosis within a few days after symptoms begin involves antigen-capture enzyme-linked immunosorbent assay (ELISA) testing, IgM ELISA, polymerase chain reaction (PCR) and Virus isolation. Clinical pictures: Initial signs and symptoms are nonspecific and may include fever, chills, myalgias, and malaise. Sufferers Address for experience nausea, vomiting, internal bleeding and organ failure Correspondence before they die. Treatment: There are no approved treatments or available Department of for Ebola virus disease (EVD) until today; however, there are a pharmacology and bunch of therapeutic approaches on the track which could have the clinical pharmacy, School of pharmacy, real impact on control and prevention of this global threat. Among college of health these, the one announced by the WHO opens some ones eyebrow and sciences, Addis Ababa gives the real glimmer of hope to tackle EVD. The two “front University, Addis running” vaccines on the track are cAd3-ZEBOV, a chimpanzee Ababa-Ethiopia. derived adenovirus vaccine developed by GlaxoSmithKline in E-mail: conjunction with the US National Institute of and Infectious [email protected] Diseases, and rVSV-ZEBOV, developed by the Agency of Canada and now licensed to a US company called New

American Journal of Phytomedicine and Clinical Therapeutics www.ajpct.org Woldu et al______ISSN 2321 – 2748

Link. Conclusions: Many promising vaccines are moving through pre- clinical or clinical trials, but mass immunization is unlikely due to the localized and sporadic nature of EBOV infections. Post- exposure interventions are therefore necessary for the treatment of cases as they occur.

Keywords: EBOV, Ebola virus, EHF, Ebola hemorrhagic fever, , Filovirus.

BACKGROUND An Ebola Hemorrhagic Fever (EHF) currently exist for preventing or treating is zoonotic pathogen caused by the filovirus infections9. Filoviridae , (EBOV)1,2. Two genera compose the family Filoviridae: Case definition for Ebola virus disease Ebolavirus and Marburgvirus3. There are (EVD) five antigenically distinct of Ebola viruses: Zaire ebolavirus (EBOV), Sudan Person under investigation (PUI) A person who has both consistent ebolavirus (SUDV), 10 (BDBV), Tai Forest ebolavirus (TAFV), symptoms and risk factors as follows : and Reston ebolavirus (RESTV) (4). All of  Clinical criteria, which includes fever of these viruses cause disease in except greater than 38.6 degrees Celsius or 101.5 RESTV, which is pathogenic in nonhuman degrees Fahrenheit, and additional primates3 (Figure 1). symptoms such as severe headache, EBOV has been endemic to sub- muscle pain, vomiting, diarrhea, Saharan Africa and has high mortality rates in abdominal pain, or unexplained humans1,2. Currently it represents a significant hemorrhage; AND challenge to global public health, causing a 1. Epidemiologic risk factors within the past severe hemorrhagic fever with case fatality 21 days before the onset of symptoms, rates of up to 90%5,6. such as contact with blood or other body Filovirus outbreak is one of the most fluids or remains of a patient fatal viral diseases worldwide affecting known to have or suspected to have EVD; humans and nonhuman primates (NHPs)7 and residence in or travel to an area where therefore, EBOV is identified as a biosafety EVD transmission is active; or direct level 4 pathogens and CDC category A agents handling of bats or non-human primates of bioterrorism6. Furthermore, the lack of from disease-endemic areas. preventive vaccines and FDA- approved therapeutics has struck fear that the Probable case EBOV could become a pandemic threat8. A PUI whose epidemiologic risk Since the identification of EBOV in factors include high or low risk exposure 10 1976, significant filovirus research has (s) . focused on developing antiviral therapies. However, despite promising vaccine Confirmed case candidates, no licensed prophylactics A case with laboratory-confirmed diagnostic evidence of Ebola virus infection10.

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Pathogenesis Once infected, humans transmit the disease through body fluids, including breast The Ebola genome milk. Funerals, which can bring dozens of The Ebola genome encodes only people in contact with the remains of Ebola seven genes, which mediate the entry, patients, are particularly dangerous and replication, and egress of the virus from the 8 gatherings for suspected victims of the virus host cell . EBOV entry requires the virion have also been outlawed12. It is also being surface-associated glycoprotein (GP) that is afraid that EBOV can become airborne13. composed of a trimer of heterodimers EBOV entry is rapid, with viral (GP1/GP2). The GP1 subunit contains two expression detectable within 2 h after heavily glycosylated domains, the glycan cap infection5. After the initial transmission, the and the mucin-like domain (MLD). The viruses can spread from person to person glycan cap contains only N-linked glycans, through contact with body fluids or whereas the MLD contains both N- and O- 14 3 contaminated needles . linked glycans (Figure 2). The of filoviruses ( The virulence nature of Ebola virus (MARV) and EBOV) are ∼19 kb, single Ebola virus enters the patient through stranded, negative sense RNA molecules mucous membranes, breaks in the skin, or encoding a total of 7 genes (NP, VP35, VP40, parenterally and infects many cell types, GP, VP30, VP24, L) separated by intergenic including monocytes, macrophages, dendritic regions of varying lengths and flanked by cells, endothelial cells, fibroblasts, untranslated regions (UTRs) at the 3′ and 5′ 9 hepatocytes, adrenal cortical cells and ends . epithelial cells. The incubation period may be 35 (VP35), encoded by related to the infection route (e.g., 6 days for filoviruses, is a multifunctional dsRNA injection versus 10 days for contact)15. binding protein that plays important roles in The virulence of EBOV can be viral replication, innate immune evasion, and attributed to several immunoevasion pathogenesis. The multifunctional nature of mechanisms: an early inhibition of innate these also presents opportunities to immunity started by the down regulation of develop countermeasures that target distinct 11 I , epitope masking and functional regions . The EBOV matrix subversion of the adaptive humoural protein is VP40, which is also found localized immunity by secreting a truncated form of the under the lipid envelope of the virus where it viral glycoprotein16. bridges the viral lipid envelope and nucleocapsid. The VP40 is effectively a Diagnosis peripheral protein that mediates the plasma The currently available screening membrane binding and budding of the virus 8 technique include wild-type or recombinant prior to egress (Figure 2&3). viruses13. Diagnosing Ebola in an person who has been infected for only a few days is Mode of transmission difficult, because the early symptoms, such as Bats have been identified as a fever, are nonspecific to Ebola infection and reservoir for Ebola viruses but it remains are seen often in patients with more unclear if transmission to an end host involves commonly occurring diseases, such as intermediate hosts. In 2013, one of the and typhoid fever10. (See table 1.) Ebola species was found in Philippine pigs Platelet counts are often decreased in raising concerns regarding animal health and the 50,000 to 100,000 range. Amylase may be food safety2.

AJPCT[2][11][2014]1287-1298 Woldu et al______ISSN 2321 – 2748 elevated, reflecting pancreatic involvement Treatment (inflammation/infection). Hepatic transami- nases are elevated with aspartate Current treatment approaches aminotransferase (AST) exceeding alanine There are no approved treatments aminotransferase (ALT); these values may available for EVD. Clinical management peak at more than 1,000 IU/L. Proteinuria should focus on supportive care of may be present. Prothrombin (PT) and partial complications, such as hypovolemia, thromboplastin times (PTT) are prolonged electrolyte abnormalities, hematologic and fibrin degradation products are elevated, abnormalities, refractory shock, hypoxia, consistent with disseminated intravascular hemorrhage, septic shock, multi-organ failure, 15 and DIC15. There is also no FDA-approved coagulation (DIC) . 10 vaccine available for Ebola . Patients with Ebola have been treated Clinical pictures 17 Patients with EVD generally have using the following measures : abrupt onset of fever and symptoms typically  Intensive fluid resuscitation (IV fluids) 8 to12 days after exposure (incubation period  Oral rehydration (drinking water) for current outbreak has a mean of  Nutritional support approximately 9 to 11 days). Initial signs and  Electrolyte (body salt) management symptoms are nonspecific and may include  Dialysis and mechanical ventilation in fever, chills, myalgias, and malaise. Due to cases of end-organ damage (failure of the these nonspecific symptoms, particularly kidneys and lungs) early in the course, EVD can often be  Pressors to maintain adequate blood confused with other more common infectious pressure and blood circulation diseases such as malaria, typhoid fever,  Blood and blood products meningococcemia, and other bacterial  Analgesics for pain relief infections (e.g., pneumonia). Sufferers  Antipyretics for fever experience nausea, vomiting, internal  Antiemetics for nausea and vomiting bleeding and organ failure before they  Antidiarrheal agents die13,15,17.  Antibiotics for accompanying infections The most common signs and symptoms reported from West Africa during Emerging targets and novel therapeutic the current outbreak from symptom-onset to approaches the time the case was detected include: fever (87%), fatigue (76%), vomiting (68%), Antibody-mediated therapeutics diarrhea (66%), and loss of appetite (65%). Currently, monoclonal antibody Unexplained bleeding has been reported from (mAbs)-based therapies are the most efficient only 18% of patients, most often blood in the at reversing the progression of a lethal Ebola stool (about 6%). Patients may develop a virus infection in nonhuman primates, which diffuse erythematous maculopapular rash by recapitulate the human disease with the day 5 to 7 (usually involving the neck, trunk, highest similarity. Novel combinations of and arms) that can desquamate. Pregnant mAbs can even fully cure lethally infected women may experience spontaneous animals after clinical symptoms and 15 miscarriages . circulating virus have been detected, days into the infection. These new developments have reopened the door for using antibody-based 18 therapies for filovirus infections .

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Monkeys which were deliberately importantly, BCX4430 completely protects infected with the Ebola virus have cynomolgus macaques from been successfully cured in a trial of a new infection when administered as late as 48 antibody drug cocktail, raising the possibility hours after infection25. of a human cure for the deadly virus19. These Experimental drugs used for sepsis cocktail of 3 different siRNAs (against L, (rAPC and rNAPc2) were the first effective VP24 and VP35) encapsulated in stable post-exposure therapies for Ebola virus nucleic acid-lipid particles (SNALPs) infection with 17% - 33% survival but provided up to 100% protection against Ebola administration required continuous virus when given 30 min post-exposure20,21. intravenous infusion20. These Monoclonal antibody (mAbs)- Investigational New Drug (IND) based therapies are becoming the most applications have been also approved by the efficient at reversing the progression of the US Food and Drug Administration (FDA) and infection in nonhuman primates, which phase I clinical trials have been initiated for recapitulate the human disease with the two small-molecule therapeutics: anti-sense highest similarity6. Such a recombinant phosphorodiamidate morpholino oligomers human monoclonal antibody directed against (PMOs: AVI-6002, AVI-6003) and lipid the envelope GP of Ebola has been nanoparticle/small interfering RNA demonstrated to possess neutralizing activity. (LNP/siRNA: TKM-Ebola)26. Therefore, Ebola neutralizing antibody may One study also come up with a be useful in vaccine development or as a successful treatment of advanced Ebola virus passive prophylactic agent22. infection with the pyrazinecarboxamide One study also showed that derivative T-705 (), in a small interleukin (IL)-10 signaling pathway animal model. The study further suggest that modulates Ebola pathogenesis. IL-10-/- mice Initiation of T-705 administration at day 6 and wild-type mice receiving antisense post infection induced rapid virus clearance, targeting IL-10 signaling via disrupting reduced biochemical parameters of disease expression through aberrant splice altering severity, and prevented a lethal outcome in were resistant to Ebola virus infection23. In 100% of the animals27. other similar study, mAbs and Ad-Vectored One study reported that st. IFN-α rescue Ebola-infected non- amiodarone, a multi-ion channel inhibitor and human primates when administered after the adrenoceptor antagonist, is a potent inhibitor detection of viremia and symptoms24. of filovirus cell entry at concentrations that are routinely reached in human serum during Other drugs and drug-like small molecules anti-arrhythmic therapy. A similar effect was A novel synthetic adenosine analogue, observed with the amiodarone-related agent BCX4430, a synthetic drug-like small dronedarone and the L-type calcium channel molecule that provides protection from Ebola blocker verapamil. Inhibition of filovirus and Marburg virus infection also reported to entry was observed with most but not all cell be effective in animal models. The study types tested and was accentuated by the pre- resulted in lower viremia, reduced clotting treatment of cells, indicating a host cell- times and reduced liver enzyme levels were directed mechanism of action28. observed in treated animals20,25. Post- One study reported that, the exposure intramuscular administration of cytoprotective enzyme heme oxygenase-1 BCX4430 protects against Ebola virus and (HO-1) such as cobalt protoporphyrin in rodent models. Most (CoPP), which acts as a selective HO-1

AJPCT[2][11][2014]1287-1298 Woldu et al______ISSN 2321 – 2748 inducer, suppresses Ebola virus replication. FDA also approved selective estrogen Since, HO-1 is an enzyme that catalyzes the receptor modulators (SERMs), including rate-limiting step in heme degradation, has clomiphene and toremifene, which act as antioxidative properties and protects EBOV potent inhibitors of EBOV infection. Anti- infected cells from various stresses as it has EBOV activity was confirmed for both of also recently shown to have antiviral activity, these SERMs in an in vivo mouse infection potently by inhibiting the replication of model. This anti-EBOV activity occurred viruses such as hepatitis C virus and human even in the absence of detectable estrogen immunodeficiency virus29. receptor expression, and both SERMs The first clinical trial of drugs to treat inhibited virus entry after internalization, Ebola virus disease is set to launch at the suggesting that clomiphene and toremifene beginning of November 2014, with first are not working through classical pathways results available by the end of the year, as per associated with the estrogen receptor32. the report by the BMJ. The partnership behind the trial, which includes Oxford University, Vaccines the International Severe Acute Respiratory Passive immunization for Ebola virus and Emerging Infections Consortium, the was successful in 2012, after over 15 years of Global Health Network, the Institut Pasteur, failed attempts leading to skepticism that the and the Institut Pasteur de Dakar, is preparing approach would ever be of potential the groundwork at record speed, having been benefit18. In fact, vaccine for EBOV was awarded a £3.2m (€4m; $5.1m) grant by the Successful in primates in 200833. Wellcome Trust at the end of September30. In 2010, vaccines have been tried in monkeys by containing pieces of the protein- Drugs targeting viral proteins sugar coat (glycoprotein) from the Zaire and Ebola virus-like particles (eVLP) Sudan EDOV, inoculated into a type of comprising of virus protein (VP40), common cold virus. Once infected, the glycoprotein, and protect monkeys' immune cells chop the Ebola rodents and nonhuman primates from lethal glycoprotein into small pieces and display EBOV infection, representing as a candidate them on their surface, where they stimulate a vaccine for EBOV infection. eVLP stimulate response from other immune cells. The the expression of proinflammatory cytokines monkeys got four "priming" shots, followed a and (IFNs) and IFN-stimulated year later with a booster shot. Four other genes (ISGs) in murine bone marrow-derived macaques got no vaccine. All eight animals dendritic cells (BMDCs) and macrophages. were inoculated with ordinarily lethal doses eVLP stimulate early innate immune of the new Ebola virus. The vaccinated responses through toll-like receptor (TLR) animals all survived, and the unvaccinated and type I IFN signaling pathways31. monkeys all died34,35. The researchers will use A number of studies have the new results to "optimize" a vaccine that demonstrated specific deletions or mutations might eventually be approved for human use. of VP40 to abrogate viral egress but to date To do that, they'll have to show it works in pharmacological inhibition of VP40 has not larger animal studies34. been demonstrated8. Functional validation The World Health Organization has and the establishment of therapeutic also said that the first vaccines against the approaches toward multifunctional proteins Ebola virus may be in use among frontline such as VP35, particularly for nonenzymatic workers in West Africa by the beginning of targets, are often challenging11. 2015. The two “front running” vaccines are

AJPCT[2][11][2014]1287-1298 Woldu et al______ISSN 2321 – 2748 cAd3-ZEBOV, a chimpanzee derived death from an EBOV infection typically adenovirus vaccine developed by occurs within 6–9 days in non-human GlaxoSmithKline in conjunction with the US primates (NHPs). This leaves a very short National Institute of Allergies and Infectious window for the treatment to reduce virus Diseases, and rVSV-ZEBOV, developed by replication until the immune response the Public Health Agency of Canada and now expands sufficiently to control the infection36. licensed to a US company called New Link30. Everyone working in the isolation area must follow the protocols and Limitations of the experimental treatments procedures. And should follow a buddy The findings of animal model studies system where should have to be responsible cannot be directly extrapolated to human use, for his/herself and the colleagues: Because because even though it is encouraging, such one mistake could be deadly37. Should wear findings must be taken with a grain of salt. protective clothing, including masks, gloves, The result has to be further repeated in gowns, and eye protection and should have to volunteer human patients or people at risk of practice proper infection control and getting the disease with a multicenter, sterilization measures, isolate patients with multination, and randomized clinical trial Ebola from other patients and should also study design. Ethical clearance and approval avoid direct contact with the bodies of people of the study from the responsible organ, who have died from Ebola10. which is still a challenging one. Multidisciplinary teams should oversee the outbreak response, address case General precautions and approaches for detection, manage cases in a dedicated unit, prevention and reintegrate convalescent patients into the General medical support is critical and community. The team should also create a should include replacement of coagulation robust risk communication, prevention, and factors and heparin if disseminated social mobilization campaign to boost intravascular coagulation develops. Such care community awareness of Ebola and how to must be administered with strict attention to prevent transmission38. The isolation area is barrier isolation. All body fluids (blood, divided into separate tents for patients with saliva, urine, and stool) contain infectious suspected, probable, and confirmed Ebola virions and should be handled with great virus infection37. care22. Practicing careful hygiene is very Livestock vaccination against Ebola important. For example, wash hands with seems currently not justified but proper soap and water or an alcohol-based hand preparedness may include experimental sanitizer and avoid contact with blood and vaccine approaches2. Resistance to Ebola body fluids. Avoid items that may have come infection is regulated by IL-10 and can be in contact with an infected person’s blood or targeted in a prophylactic manner to protect body fluids (such as clothes, bedding, needles, against lethal hemorrhagic virus challenge23. and medical equipment). Avoid funeral or Many promising vaccines are moving burial rituals that require handling the body of through pre-clinical or clinical trials, but mass someone who has died from Ebola. Avoid immunization is unlikely due to the localized contact with bats and nonhuman primates or and sporadic nature of EBOV infections. blood, fluids, and raw meat prepared from Post-exposure interventions are therefore these animals15. necessary for the treatment of cases as they occur, but have been harder to develop as

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CONCLUSION Pharmacy, College of Medicine and Health Sciences, Ambo University; Early recognition is critical for Ambo- Ethiopia. Email: jimmapharm@ infection control. Health care providers gmail.com. should be alert for and evaluate any patients 3. Gobezie Temesgen Tegegne: suspected of having EBOV. Many promising  BPharm, MSc in Clinical Pharmacy, vaccines are moving through pre-clinical or fulltime Lecturer: department of clinical trials, but mass immunization is Pharmacy, College of Medicine and unlikely due to the localized and sporadic Health Sciences, Ambo University; nature of EBOV infections. Post-exposure Ambo- Ethiopia. Email: gobepharm@ interventions are therefore necessary for the gmail.com. treatment of cases as they occur. 4. Gizaw Dabessa Satessa:  BSc, MD., fulltime Lecturer: department Competing interests of Pharmacy, College of Medicine and The Authors’ declare that there are no Health Sciences, Ambo University; competing interests. Ambo-Ethiopia. Email: gizaw_dhab@ yahoo.com. Authors’ contributions MAW has made substantial ACKNOWLEDGMENTS contributions to conception and gathering of information and has been involved in drafting The authors’ are grateful to all the the manuscript or revising it critically for health care professionals, researchers and important intellectual content; and has given governments working to prevent this global final approval of the version to be published. terror risking their life, family and JLL has made substantial contributions to community. We are also grateful to all the conception and design, or acquisition of data, information resources included in this review or analysis and interpretation of data. GTT article with specially thanks to NIH, NEJM has been involved in drafting the manuscript and BMJ. or revising it critically for important intellectual content. GDS has been involved Operational definitions in drafting the manuscript or revising it critically for important intellectual content. EVD exposure risk levels All Authors read and approved the final Levels of exposure risk are defined as 10 manuscript. follows :

Author information High risk exposures 1. Minyahil Alebachew Woldu: A high risk exposure includes any of  BPharm, MSc in Clinical Pharmacy, the following: fulltime Lecturer: department of  Percutaneous (e.g., needle stick) or Pharmacology and Clinical pharmacy, mucous membrane exposure to blood or College of Medicine and Health Sciences, body fluids of EVD patient Addis Ababa University; Addis Ababa-  Direct skin contact with, or exposure to Ethiopia. Email: [email protected]. blood or body fluids of, an EVD patient Tel: +251-91-2648527. without appropriate personal protective 2. Jimma Likisa Lenjisa: equipment (PPE)  BPharm, MSc in Clinical Pharmacy,  Processing blood or body fluids of a fulltime Lecturer: department of confirmed EVD patient without

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appropriate PPE or standard biosafety ELISA - Enzyme-Linked Immuno- precautions sorbent Assay  Direct contact with a dead body without EVD - Ebola Virus Disease appropriate PPE in a country where an GP - Glycoprotein EVD outbreak is occurring mAbs - Monoclonal Antibody MARV - Marburg Virus Low risk exposures MLD - Mucin-like Domain A low risk exposure includes any of NHPs - Nonhuman Primates the following. PCR - Polymerase Chain Reaction  Household contact with an EVD patient PT - Prothrombin  Other close contact with EVD patients in PTT - Partial Thromboplastin Times health care facilities or community PUI - Person under investigation settings. Close contact is defined as, RESTV - Reston Ebolavirus 1. Being within approximately 3 feet (1 SUDV - meter) of an EVD patient or within the TAFV - Tai Forest Ebolavirus patient’s room or care area for a prolonged period of time (e.g., health care REFERENCES personnel, household members) while not wearing recommended personal 1. Eri Nakayama, Saijo M. Animal models for protective equipment (i.e., standard, Ebola and Marburg virus infections. Frontiers droplet, and contact precautions; in Microbiology | Virology 2013; 4:1-20. see Infection Prevention and Control 2. Feldmann F, H. F. Ebola: facing a new Recommendations). transboundary animal disease? Dev Biol (Basel) 2013; 135:201-9. 2. Having direct brief contact (e.g., shaking 3. Lennemann NJ, Rhein BA, Ndungo E, hands) with an EVD patient while not Chandran K, Qiu X, W. M. Comprehensive wearing recommended personal functional analysis of N-linked glycans on protective equipment. Ebola virus GP1. MBio 2014 5:e00862-13.  Brief interactions, such as walking by a 4. Heinz Feldmann. Ebola - A Growing Threat? person or moving through a hospital, do N engl j med 2014. not constitute close contact. 5. Hoenen T1, Groseth A, Callison J, Takada A, H. F. A novel Ebola virus expressing No known exposure luciferase allows for rapid and quantitative Having been in a country in which an testing of antivirals. Antiviral Res 2013; 99:207-13. EVD outbreak occurred within the past 21 6. Qiu X1 KG. Antibody therapy for Ebola: Is days and having had no high or low risk the tide turning around? Hum Vaccin exposures. Immunother 2014 6:4. 7. Marzi A, H. F. Ebola virus vaccines: an Acronyms and abbreviations overview of current approaches. Expert Rev ALT - Alanine Aminotransferase Vaccines 2014; 13:521-31. AST - Aspartate Aminotransferase 8. Stahelin RV. Could the Ebola virus matrix BDBV - Bundibugyo Ebolavirus protein VP40 be a drug target? Expert Opin DIC - Disseminated Intravascular Ther Targets 2014 18:115-20. Coagulation 9. Uebelhoer LS, Albariño CG, McMullan LK, EBOV - Ebolavirus et al. High-throughput, luciferase-based reverse genetics systems for identifying EHF - Ebola Hemorrhagic Fever inhibitors of Marburg and Ebola viruses. Antiviral Res 2014; 106:86-94.

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disease - firestone district, liberia,. MMWR Morb Mortal Wkly Rep 2014; 63:959-65.

Table 1. Laboratory tests used in diagnosis include10

Timeline of Infection Diagnostic tests available Antigen-capture enzyme-linked immunosorbent assay (ELISA) testing Within a few days after IgM ELISA symptoms begin Polymerase chain reaction (PCR) Virus isolation Later in disease course or IgM and IgG antibodies after recovery Immunohistochemistry testing Retrospectively in deceased PCR patients Virus isolation

Figure 1. Outbreaks or episo des of filovirus Infections4

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Figure 2. Linear model of EBOV glycoprotein. The disulfide bond between GP1 and GP2 is indicated, as well as the locations of N-linked glycans (marked with “Ys”) in the GP1 and -2 domains, and the known protease cleavage sites are noted. SP, signal peptide; RBD, receptor- binding domain; MLD, mucin-like domain; IFL, i nternal fusion loop; HR1 and -2, heptad repeats 1 and 2; TM, transmembrane domain3

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