National Institutes of Health



Genevieve BruenMay 6, 2019Ebola Virus Review In the 2014-16 outbreak of Zaire ebolavirus, referred to as Ebola virus, in West Africa there were 28,652 cases of infection and approximately 11,325 deaths (“2014-2016 Ebola Outbreak in West Africa”). Since August 2018, the current Ebola virus outbreak in the Democratic Republic of Congo (DRC) has caused confirmed infections in 1,488 people, resulting in 1,029 deaths as of this writing (Ebola situation reports: Democratic Republic of the Congo”). The number of Ebola virus infections and deaths in the DRC continues to rise rapidly.Ebolaviruses are an aggressive genus of viruses that belong to the family Filoviridae. There are four species of Ebolavirus that have the ability to cause disease in humans including: Ebola virus (Zaire ebolavirus), Bundibugyo ebolavirus, and Sudan ebolavirus (Malvy et al. 936). Ta? Forest ebolavirus, a fourth species of ebolavirus, has only been responsible for one human infection (“Ebola Virus Disease Distribution Map”). Ebola virus has a single strand of negative sense RNA (Malvy et al. 936). Negative sense means that in order for the virus to be replicated, it must be converted into the proper form of RNA first (Cowan, Smith and Lusk 130). Ebola virus can cause severe Ebola Virus Disease (EVD) that can be fatal. Total case fatality for Ebola virus (Zaire ebolavirus) has been 80% (Malvy et al. 936). It is important to learn about Ebola’s structure, how it causes disease, the symptoms it causes, and how the virus is spread so that we can develop better ways to prevent it.In order to understand the way Ebola virus causes disease and how to prevent it, researchers study the viral structure and how the structure influences the virus’s ability to enter the cell and cause disease. Ebola contains seven proteins referred to as Viral Proteins (VP), a single strand of RNA, viral glycoproteins, and an envelope membrane (Goodsell 1). The matrix protein of the Ebola is made up VP 40 which provides structural integrity to the Ebola virion (Falasca et al. 1251). The matrix also enables replicated virions to be released from the host cell by a process called budding (Rivera and Messaoudi 186). “The matrix protein of ebola is particularly unusual because it adopts entirely different structures for its different jobs: as a hexamer in the virion structure, as an octamer that binds to RNA and regulates viral transcription, and as a dimer involved in transport of the protein” (Goodsell 2). Ebola’s matrix protein takes on different shapes to serve different functions during the various stages of the infection (Gnida).The nucleocapsid is formed by VP35, VP30, and VP25 (Goodsell 1). The nucleocapsid wraps around the RNA and protects it (Goodsell 2). Its structure looks wavy because of its filamentous structure and its viral proteins interactions are not rigid (Goodsell 2). The L protein in the Ebola virion creates new copies of the RNA when the virus is replicated inside of the host cell. The envelope membrane is “stolen” from host cells (Goodsell 1).The entrance of Ebola virus into the host cell involves the viral glycoproteins, the receptors on host cells that are tropisms for the virus, and certain mechanisms involved. Entry into a host cell is intregal to the virus’s ability cause disease, because the Ebola virus must enter into cells and use their machinery to replicate and cause disease. The viral glycoprotein of Ebola protrudes from the surface of the virus and is covered with carbohydrate to conceal it from the immune system (Goodsell 1). The glycoprotein binds receptors on the tropism cells of the host, which are the target tissues. According to Dr. Goodsell, the binding of the glycoprotein to the receptor causes a shape change that drags the Ebola virus close enough to the host cell for the membranes to fuse together, allowing the virus to enter into the cell (1). Other methods used by Ebola virus to enter into target cells after binding receptors are macropinocytosis and receptor-mediated endocytosis (Falasca et al. 1251). Macropinocytosis involves the cell “drinking-in” extracellular fluid and the nearby molecule, in this case Ebola virus. Receptor-mediated endocytosis occurs when the host cell engulfs the Ebola virus. All the receptors that are involved in Ebola virus internalization are not known, but two of them have been identified. Niemann-Pick C1 (NPC1), an endosomal protein on host cells, has been shown to be an entry receptor that primes the virus glycoprotein for fusion of membranes and binds to ebolavirus (Wang et al. 258). The T-cell immunoglobulin and mucin domain 1, TIM-1, on host cells is a binding site for Ebola virus and is found on many human cells (Kondratowicz et al. 8426).There are a wide range of target cells, known as tropisms, that the Ebola virus can infect. The target cells it attacks lend some insight into the damage that Ebola inflicts. Ebola has shown the ability to infect monocytes, macrophages, dendritic cell, hepatocytes, endothelial cells and fibroblasts in humans (Falasca et al. 1252). Since Ebola virus infects several important immune system cells, the monocytes, macrophages and dendritic cells, it deregulates the immune system which makes it harder to fight. Normally, dendritic cells function as Antigen Presenting Cells, which phagocytize pathogens and then alert T-cells that there is a pathogen that must be destroyed (Malvy et al. 939). When dendritic cells are infected, they fail to alert T-cells of Ebola’s presence. Without the ability to recognize there is a problem, T-cells and antibodies cannot attack the Ebola virus, leaving the virus with the ability to continue to spread and infect (Rivera and Messaoudi 186). Dendritic cells also fail to mature when infected, which suppresses type I Interferon (Falasca et al. 1254). Type I Interferon would typically bind receptors of nearby cells to prevent them from becoming infected but are unable to do so when suppressed. Ebola infected monocytes and macrophages stimulate a cytokine storm that causes the release of many inflammatory molecules called cytokines (Falasca et al. 1254). The high level of cytokines and nitric oxide causes apoptosis of lymphocytes (Rivera and Messaoudi 186). High levels of cytokine and the nitric oxide can also trigger deregulated hemostasis: leading to coagulation, vascular damage and loss of the blood vessel’s structural integrity (Falasca et al. 1254). This damage is partly responsible for the hemorrhaging seen in some people suffering from Ebola. The other element responsible for hemorrhaging is the infection of the liver’s hepatocytes. When the hepatocytes are infected with Ebola, the liver is less able to produce coagulation proteins and other elements of the plasma (Servick 2). It must also be noted that Ebola can damage the adrenal gland and the gastrointestinal tract, which causes dehydration, resulting in a dramatic drop in blood pressure that can prevent organs from getting the oxygen they need (Servick 2).There are many severe signs and symptoms caused by Ebola Virus Disease. Symptoms start after the virus is incubated in the human host for 2 to 21 days (Malvy et al. 939). Common signs and symptoms that are experienced in the beginning of the disease are high fevers, fatigue, severe headache, body aches, rash and joint pain (Malvy et al. 939). These symptoms are similar to that seen in many other illnesses that are endemic in countries in West Africa and the DRC, so they are commonly attributed to malaria and similar illnesses. A few days after becoming symptomatic, gastrointestinal illness sets in causing vomiting, diarrhea and dehydration (Malvy et al. 939). Following the gastrointestinal stage, patients who do not recover may experience low blood volume causing them to go into shock; this is partly due to the aforementioned loss of the blood vessel’s structural integrity and widespread inflammation. This stage may also cause hemorrhaging, ranging in severity and types (Malvy et al. 939). Blood loss and the deprivation of oxygen to critical organs often result in death if left untreated. There are other symptoms and signs caused by Ebola that are rare, such as encephalitis and cardiac arrythmia (Malvy et al. 939). The high case fatality of Ebola Virus Disease is linked to severe signs and symptoms that don’t receive adequate and aggressive treatment (Malvy et al. 936).Ebola virus is first transmitted from animal to human, and then it is transmitted from human to human (“Transmission Ebola Hemorrhagic Fever”). Scientists believe that the natural reservoir of Ebola virus is a fruit bat or a nonhuman primate (“Transmission Ebola Hemorrhagic Fever”). Typically, the spread from animals to humans occurs by ingestion of infected bushmeat or exposure to bat droppings (“Transmission Ebola Hemorrhagic Fever”). The virus is found in bodily fluids and is spread through direct contact with these fluids (“Transmission Ebola Hemorrhagic Fever”). The virus can enter through broken skin or any mucous membrane. Bodily fluids containing Ebola can be “urine, saliva, sweat, feces, vomit, breast milk and semen” (“Transmission Ebola Hemorrhagic Fever”). Usually, the virus is only transmissible once a person shows signs and symptoms of Ebola Virus Disease (“Transmission Ebola Hemorrhagic Fever”). However, the virus can live and persist in a person’s semen, breastmilk, eye fluid and cerebrospinal fluid after they have recovered from infection (“Transmission Ebola Hemorrhagic Fever”). This means that unprotected sex and breastfeeding can spread Ebola to new individuals after the recovery of an infected person. The virus is at its most transmissible when a person is experiencing their worst symptoms and after death (“Transmission Ebola Hemorrhagic Fever”). Unproperly sterilized or disinfected medical equipment can also harbor the Ebola virus (“Transmission Ebola Hemorrhagic Fever”). Since the Ebola virus is easily transmitted, care must be taken to prevent it’s spread.There are straightforward guidelines to prevent the spread of Ebola, but there are many barriers that make prevention difficult. It is important to have good hygienic practices such as thorough hand washing and avoiding contact with body fluids and objects that have come into contact with fluids of infected individual (Beeching et al. 10). When a person dies of a disease that is similar to one of Ebola, funeral and burial practices should avoid physical contact with the person’s body (Beeching et al. 10). Beeching et al. recommend that humans should try to avoid physical contact with bats and nonhuman primates and their bodily fluids. If a person decides to ingest meats from these animals, commonly referred to as bushmeat, it is very important to cook the meat thoroughly and avoid contamination of non-cooked food and utensils (Beeching et al.). For healthcare workers, there are specific steps to follow to prevent spreading the Ebola virus. First, personal protective equipment (PPE) should be worn when treating a patient that is suspected of having Ebola Virus Disease (EVD). PPE that are mandatory for the treatment of patients include: single use impermeable gown with leg coverage, either an N95 respirator mask or PAPR respirator to protect face and airway, long cuff gloves, single use boot covers, and a disposable apron (“Guidance on Personal Protective Equipment”). It is important to properly put on and take off the PPE to avoid exposure contamination. Proper sterilization and disinfection of all surfaces and instruments that come in contact with an individual are required (Beeching et al. 10). Early identification and diagnosis of Ebola virus and isolation of those who are suspected of the virus is very important. Once a case of Ebola is suspected, it is important to trace all the persons that the patient has come into contact with and monitor them for symptoms for at least 21 days, a practice known as contact tracing (Beeching et al. 12). Education of people who may be exposed to the virus is important to lessen the chance of them contracting the virus.There are many barriers that have made it difficult to prevent the spread of Ebola including barriers to early diagnosis and isolation, fear, distrust of medical professionals, burial practices, inadequate number of supplies and healthcare providers, and violence. Diagnostic capacity has been poor because of a lack of infrastructure (Malvy et al. 936), which has made it difficult to confirm cases and contact trace (“Barriers to rapid containment of the Ebola outbreak” 1). Also, since early EVD symptoms mimic common regional infections like malaria, early isolation and monitoring of potentially infected individual has been difficult. Perhaps the largest barriers to effective isolation of Ebola is the fear and distrust that people feel towards treatment facilities, medical workers, and the government (“Barriers to rapid containment of the Ebola outbreak” 2.) During the Ebola outbreak in West Africa, the medical response followed scientific methods of containment, but often failed to respect cultural and religious beliefs (Manguvo and Mafuvadze 1). Fear of community outreach workers has also been made worse in the DRC, when armed security forces accompanied the workers and forced vaccination on at-risk populations (Nguyen 1299).Also, victims of Ebola and families have feared dying in treatment centers and being separated from family members, so they have fled from treatment centers and hid symptomatic family members (“Barriers to rapid containment of the Ebola outbreak” 2). Burial practices hold enormous religious and traditional significance to many communities in West Africa and the DRC (Manguvo and Mafuvadze 2).Many believe that it is the surviving family’s responsibility to usher the dead family members into life after death by certain ceremonial practices. Traditional beliefs state that failure to complete these practices can result in the dead spirit coming back to torment living relatives (Manguvo and Mafuvadze 2). The burial process often include washing and then touching the face of the deceased (Manguvo and Mafuvadze 2). In Guinea, one of the West African countries devastated by Ebola, 60% of the Ebola cases have been linked to burial practices (“Barriers to rapid containment of the Ebola outbreak” 2). Mistrust and fear were further fostered when burials were conducted by medical workers without the notification and consent of relatives, leading some families to fear that bodies were being used by Westerners for personal gain or immoral purposes (Manguvo and Mafuvadze 1). Often in regions affected by Ebola, there has been an insufficient supply of Personal Protect Equipment (PPE) and disinfectant making the spread to healthcare workers and others more prevalent (“Barriers to rapid containment of the Ebola outbreak” 1). The “hot and cumbersome” nature of PPE that medical staff must wear, make it impossible to work more than 4 hours at a time without having a 2 hour break to rehydrate and rest (“Barriers to rapid containment of the Ebola outbreak” 2). Leligdowicz et al. state that the PPE cannot be safely worn over 45-60 minutes because of the heat and humidity (3). There have been several violent attacks on Ebola Treatment Centers and medical personnel during the current outbreak in the DRC (Nguyen 1298). Many of these attacks have been in the “epicenter of the epidemic” and some resulted in closed treatment centers, injuries, and a fatality (Nguyen 1298). The reasons for the attacks often remain unclear, but they may be fueled by anger and fear over events where armed agents have forced patients into treatment centers, the belief that outsiders are benefiting from the Ebola epidemic, and political unrest (Nguyen 1299).Removing barriers to treatment and containment of Ebola virus is essential to preventing its spread. Using the Real-Time PCR test, early diagnosis that can allow for quicker isolation is possible (Malvy et al. 938). Doctors without Borders, MSF, have been working to combat fear and distrust by building relationships with communities that have been affected with Ebola (Nguyen 1298). An important way they are achieving this is by engaging chiefs and leaders in the community (Nguyen 1299). They have made efforts to answer questions in the communities truthfully and to treat people who are suffering from diseases unrelated to EVD. This strategy is meant to build trust by showing communities that treatment centers are concerned with the overall wellbeing of people in DRC, not just in Ebola. It also reduces the fear that Westerners are trying to profit off of Ebola victims. Another way to reduce fear of medical outreach workers is to make vaccines optional and not forced by security forces (Nguyen 1299). In regions that have had forced vaccinations, noncompliance has been high, yet in communities where armed security wasn’t present to force vaccinations, the vaccination rate has been extremely high (Nguyen 1299). In order for containment plans to be successful, these plans must respect and work with the cultural beliefs of communities and individuals with Ebola. Educating chiefs and religious leaders on prevention methods, and then allowing them to determine ways to follow guidelines of prevention while still respecting their culture and beliefs will hopefully prove an effective way to contain the spread of Ebola. (Manguvo and Mafuvadze 1). There is a need for the engineering of less costly Personal Protective Equipment that is more effective in keeping those treating and interacting with Ebola patients from overheating while providing greater safety (Leligdowicz et al. 10). This will hopefully combat the shortage of PPE and increase the quality of treatment given to patients.It is my hope that a combination of cultural respect, medical science, improved equipment, and more medical supplies will prevent Ebola from causing such widespread suffering and death. References1.2014-2016 Ebola Outbreak in West Africa | History | Ebola (Ebola Virus Disease) | CDC. (2019). at \2. Ebola situation reports: Democratic Republic of the Congo. Who.int (2019). At Virus Disease Distribution Map: Cases of Ebola Virus Disease in Africa Since 1976. (2019). at , M., Smith, H. & Lusk, J. Microbiology fundamentals: a clinical approach. 130 (McGraw-Hill Education, 2019).5.Malvy, D., McElroy, A., de Clerck, H., Günther, S. & van Griensven, J. Ebola virus disease. The Lancet 393, 936-939 (2019).6.Goodsell, D. PDB101: Molecule of the Month: Ebola Virus Proteins. RCSB: PDB-101 (2019). at , L. et al. Molecular mechanisms of Ebola virus pathogenesis: focus on cell death. Cell Death & Differentiation 22, 1251-1254 (2015).8.Rivera, A. & Messaoudi, I. Pathophysiology of Ebola Virus Infection: Current Challenges and Future Hopes. ACS Infectious Diseases 1, 186 (2015).9.Gnida, M. 'Transformer' protein provides new insights into Ebola virus disease. (2019). at <, H. et al. Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1.?Cell?164, 258 (2016).11.Kondratowicz, A. et al. T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus.?Proceedings of the National Academy of Sciences?108, 8426 (2011).12.Servick, K. What does Ebola actually do?.??(2014). at Ebola Hemorrhagic Fever.??(2019). at , N., Fenech, M., Fletcher, T. & Houlihan, C.?BMJ Best Practice: Ebola virus infection. 10-11 (BMJ Best Practice, 2019). at on Personal Protective Equipment (PPE).??at to rapid containment of the Ebola outbreak.?Who.int?(2014). at Manguvo, Benford Mafuvadze. The impact of traditional and religious practices on the spread of Ebola in West Africa: time for a strategic shift. Pan Afr Med J. 2015;22(Supp 1):9Angellar Manguvo, Benford Mafuvadze. The impact of traditional and religious practices on the spread of Ebola in West Africa: time for a strategic shift. Pan Afr Med J. 2015;22(Supp 1):9Angellar Manguvo, Benford Mafuvadze. The impact of traditional and religious practices on the spread of Ebola in West Africa: time for a strategic shift. Pan Afr Med J. 2015;22(Supp 1):9Angellar Manguvo, Benford Mafuvadze. The impact of traditional and religious practices on the spread of Ebola in West Africa: time for a strategic shift. Pan Afr Med J. 2015;22(Supp 1):917.Manguvo, A. & Mafuvadze, B. he impact of traditional and religious practices on the spread of Ebola in West Africa: time for a strategic shift.?PanAfrican Medical Journal?22(Supp 1):9, 1-2 (2015).18.Nguyen, V. An Epidemic of Suspicion — Ebola and Violence in the DRC.?New England Journal of Medicine?380, 1298-1299 (2019).19.Leligdowicz, A. et al. Ebola virus disease and critical illness.?Critical Care?20, 3 (2016). ................
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