Ebola Hemorrhagic Fever Outbreak In Uganda Biology Essay


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Ebola Hemorrhagic Fever (EHF) is an endemic African disease caused by infection with Ebola virus (EBOV). Outbreaks are sporadic and highly fatal. An outbreak of EHF subtype Sudan was reported in the Kibaale district in western Uganda this past July with a fatality rate of 71%. The background of this disease will be discussed in depth in order to provide an accurate foundation for investigation of the outbreak in question. Taxonomy, viral structure, replication cycle, and pathogenesis will be examined to better understand the virus at the root of the outbreak. The search for EBOV's reservoir, viral transmission, patient treatment, outbreak identification and containment, and prevention will also be considered.

EBOV is a member of the family Filoviridae composed of viruses with a filamentous shape. These viruses are enveloped, non-segmented, negative-stranded RNA viruses and reside within the order Mononegavirales (1). Marburg virus is also included within the family Filoviridae. Five distinct species of Ebola virus are known to exist, each named after their place of discovery, which include: Zaire ebolavirus, Sudan ebolavirus, Cote d'Ivoire ebolavirus, Bundibugyo ebolavirus, and Reston ebolavirus. Phylogenetic analysis of glycoprotein amino acid sequences of the above filoviruses has been completed to determine their relation. Sudan ebolavirus, the strain responsible for the outbreak of EHF in Uganda this past July, was determined to be a sister taxon to Reston ebolavirus, the only subtype that does not infect humans. Zaire ebolavirus, Cote d'Ivoire ebolavirus, and Bundibugyo ebolavirus compose their sister clade (2). Marburg virus appears to have diverged from Ebola virus about 7,000 years ago based on the degree of sequence divergence between the two viral genera (3). Each species of EBOV is structurally very similar.

The nucleocapsid (NC) of Ebola virus form a left-handed helix and is enclosed in an envelope derived from the host cell membrane. The inner nucleoprotein layer of the NC is composed of VP24 and VP35. The envelope is studded with one glycoprotein. The virions form filaments 80 nm in diameter and approximately 920 nm in length, but may assume other shapes (4). It appears that the inner diameter of the NC is defined by the N-terminal region of the nucleoprotein and the length is delineated by the size of the genome. The single-stranded, negative-sense RNA genome encodes seven structural proteins. These proteins are encoded by a genome of 19 kb in the following order: nucleoprotein (NP), polymerase cofactor (VP35), matrix protein (VP40), glycoprotein (GP), replication-transcription protein (VP30), minor matrix protein (VP24), and RNA dependent-RNA polymerase (L). Ebola virus also expresses one glycoprotein that is secreted (sGP) due to an evolutionary development that utilizes the start-stop method of transcription along the GP region of the genome (5, 6).

EBOV uses a number of mechanisms to reproduce while utilizing host cell machinery. Like many RNA viruses, Ebola uses RNA dependent RNA polymerase to assist in transcription and other steps of the viral replication cycle in the cytoplasm of the infected cell. In the initial steps of replication, it makes a short and long version of mRNA through different mechanisms. The virus has an essential glycoprotein (GP) which plays an important role as a surface receptor that initiates attachment, targeting phagocytes, hepatocytes, and endothelial cells (1).

Ebola is able to attach to the surface of the host cell via its GP. The GP is thought to interact with several C- type lectin surface receptors found on dendritic cells and macrophages. Two of the recognized receptors are dendritic cell-specific intercellular adhesion molecule ICAM-3 grabbing non-integrin (DC-SIGN) molecule and Liver/ lymph node-specific ICAM-3 grabbing non-integrin (L-SIGN) (2). It is proposed that the C-type lectin receptors assist the GP with attachment and infection of the target cell. Upon attachment of the Ebola virus, it is known that the GP protein undergoes a series of conformational changes which are critical for the entry of the virus (3).

Ebola uses the GP protein to gain entry into the cytoplasm of the host cell. Entry is dependent upon pH and occurs by endocytosis via the clathrin protein. The Ebola virion fuses with the plasma membrane as it enters the host cell, causing a drop in the pH. This fusion event causes the formation of an endocytic vesicle and conformational changes in the envelope (1). The clathrin protein is positioned in a way that a pit forms on the internal side of the plasma membrane. Other essential proteins involved in the entry of Ebola are the Adaptor Protein complex-2 (AP-2) as well as the epidermal growth factor receptor (EGFR) pathway substrate clone 15 (Eps15) (4). The virus is then extruded into the host's cytoplasm for further replication.

Uncoating is consistent with the current data for viruses that enter by an endocytotic vesicle. The typical mechanism for Ebola is that it fuses with a vesicle contingent upon a low pH. The acidification of the vesicle causes a conformational change, cleavage of the glycosylated GP by cellular Cathepsin, resulting in fusion of the virus. The protein Niemann Pick C1 is located in the membrane of the endosome and interacts with the cleaved GP promoting infection. Uncoating takes place in the cytoplasm where the genome is released, transcribed, and later replicated (1).

Ebola replicates and transcribes in the cytoplasm of the host cell. The virus uses the L protein to assist with replication which is considered to serve a similar function as RNA dependent RNA polymerase (1). The L protein is attached to the 5' end of Ebola's genome. Additionally, the RNA dependent RNA polymerase uses VP35 as a cofactor to convert the negative strands into positive monocistronic strands (5). Transcription begins with the production of multiple positive GP mRNAs and short sGP mRNAs. The longer GP mRNA is the result of an error in the translation process, but yields the correct version of the GP protein (5). The shorter version is made most frequently within infected cells. The longer version of the GP mRNA is made by an RNA editing and frameshifting system. RNA editing is performed by the insertion of one adenosine nucleotide into the seven codon genome by the polymerase. Therefore, the stop codon is shifted, and the positive strand is no longer complementary to the negative strand. Similarly, frameshifting occurs via a stuttering event by the ribosomes due to the long run of mRNA adenosines. The ribosomes shift as translation is taking place, resulting in the GP (5).

Translation is completely reliant on the host cell's ribosomes. Because Ebola is an RNA virus, translation occurs in the cytoplasm of the cell (1). After the ribosomes translate the GP mRNA into protein, the virus is directed to the endoplasmic reticulum (ER) of the cell for initiation of exocytosis. Genome replication is initiated by the L protein once the amount of translated GP reaches the correct concentration. This intermediate is essential for negative RNA stranded viruses. Ebola converts negative strands into positive strand intermediates, using the positive strands as a template to make more negative stranded RNA for progeny virions (5).

Ebola uses a number of proteins for the assembly process leading to the encapsidation of the virus. The NC is assembled as NP binds to the RNA, forming a loose coil, which is then condensed as VP40 binds to the NP. Rigidity is granted to the NC through the alternate binding of VP24 and VP35 to the NP (Allison 5, 6). VP40 is known to facilitate the production of viral-like proteins and serves essential functions in both capsid assembly and budding of the virus (6). After translation, GP navigates through the ER where it begins the initial steps of exocytosis (5). Ebola buds off the surface of the plasma membrane obtaining its envelope from the host upon exiting the cell. The proteins VP40 and VP24 are used for the budding process and structural stability (7). The virus is completely assembled and able to infect other cells of the host following egress.

The lethality of EBOV is related to several tactics that evade and exploit the immune system. The period of incubation ranges from two to twenty-one days depending on the strain. This virus causes systemic damage since it binds and replicates in an enormous number of cell types. Efficient replication in monocytes prompts a response similar to sepsis as proinflammatory cytokines elicit a cytokine storm eventually resulting in Disseminated Intravascular Coagulation (DIC). Because of the high amount of virions in the body and massive cell infection, the cytokines responsible for inflammation are released by nearly every cell in the body (Bray, 2005). The pathogenesis of Ebola virus is closely related to the role and structure of GP, which may aid in immune system evasion and immunosuppression of the major histocompatibility complex. VP35 may serve as an interferon antagonist and play a pivotal role in viral RNA synthesis. The potency of VP35 may shed light on the varying degrees of virulence between the Ebola strains (5, 6 Allison).

Initial pathogenesis is exacerbated as the virally induced cytokine release causes diapedesis, which allows leukocyte extravasation across intact capillary walls, and inhibits clotting factors (Bray, 2005). This combination causes a systemic inflammatory response syndrome and edema. Extensive tissue necrosis of the lungs, liver, lymph nodes, and spleen occur as a result of viral cytopathogenesis. The hemorrhagic component of the disease is a consequence of vascular injury caused by viral glycoproteins breaking down host endothelial cells. Leaky capillaries and reduced available clotting factors cause internal and external hemorrhage. Extensive hemorrhage is followed by edema and hypovolemic shock. The resulting drop in blood pressure and hypovolemic shock leads to organ failure, as vital organs throughout the body are unable to receive oxygen (Parham, 2000).

Among the cytokines produced are endogenous pro-inflammatory pyrogens, Interleukins 1 and 6 (IL-1, IL-6) as well as Tumor Necrosis Factor α (TNFα). Collectively this group causes fever by resetting the thermostat in the hypothalamus. These cytokines are also responsible for increasing the number of macrophages in the blood and later guide the phagocytes to secondary lymphoid tissue (Parham, 2000). Because EBOV infects phagocytes, the body's immune response inadvertently aids in the spread of the virus (Bray, 2005). In an effort to activate adaptive immunity, the macrophages effectively deliver the virus to the lymphatic system and consequently to the rest of the body. The blood-brain barrier works to maintain the separation of extracellular fluid of the central nervous system and circulating blood. The normally tight junctions between endothelial cells become more permeable with massive inflammation to permit macrophages to patrol and phagocytize pathogens. In the case of EHF, virus laden macrophages enter the brain and erupt. At this stage patients have severe headaches, encephalitis, and become unresponsive (Bray, 2005).

The majority of EHF outbreaks occur in the most remote and resource poor regions of sub-Saharan Africa. These areas lack a healthcare delivery system and their infection control standards are deprived. Cases for EHF can be identified by the display of a series of heightened symptoms as the virus increases replication. Initial infection takes around eight days to see the onset of abrupt flu-like symptoms such as fever, chills, headache, anorexia, and joint pains. These signs may be misinterpreted as Malaria, causing the infected person to delay seeking treatment. Gastrointestinal signs emerge within a few days. The patient experiences nausea and vomiting, diarrhea, and a characteristic abdominal tenderness in the right upper quadrant commonly seen in EHF infections. Within these EHF infections, an abnormal enlargement of the spleen and liver or hepatosplenomegaly can also develop. Hiccups may also be observed and can be the result of diaphragm irritation, thus resulting in a poor prognosis (Bausch, 2008).

If the disease evolves to a more severe prognosis, usually after nine days of clinical symptoms, the EBOV infection can lead to vascular instability showing signs of facial flushing, edema, hypotension, shock, and hemorrhage from mucous membranes. At this point in the disease, infected individuals will normally vomit blood or discharge blood out the rectum. Unlike other hemorrhagic fevers, blood is not coughed up. Cutaneous presentation may include maculopapular rashes, petechiae, ecchymoses, and hematomas around injection or intravenous catheter sites. The virus manages to disrupt blood coagulates, which results in this immense blood leakage (Bausch, 2008). Death is usually the result of multiple organ failure due to DIC, focal tissue necrosis, and fluid redistribution leading to hypotension. The emergence of the more fatal symptoms could be a result from the conditions found in sub-Saharan Africa. The Center for Disease Control (CDC) advises that there is no standard treatment given for Ebola hemorrhagic fever. Traditionally, patients receive supportive therapy consisting of increasing fluids and electrolytes, maintaining oxygen and blood levels, and treating secondary infections (CDC, 2010).

Epidemics in sub-Saharan Africa face a poor patient setting, a lack of local healthcare workers, and a community stigma that are all detrimental to attempts for outbreak containment. Patients cannot be properly treated because there is a lack of multi-bed units, little running clean water, limited antimalarials and antibiotics, and a rudimentary diagnostics lab. Lab confirmations have to be sent to other parts of the world, which usually is a lagged process coming from these sub-Saharan clinics. Consequently, results from international labs typically takes months following the initial infections of the community. Therefore, the lack of resources, non-aseptic conditions, and prolonged results contribute to further spread of the virus (Bausch, 2008).

Ebola virus infects humans via zoonotic transmission. It is hypothesized that patient zero in an outbreak contracts the virus through contact with an infected animal either through hunting or scavenging of infected carcasses (Special Pathogens Branch). The virus may be transmitted from the index case to other humans though direct contact with infected blood or secretions of other bodily fluids. The people most likely to become exposed to the virus are close family members and healthcare professionals who are caring for the sick individuals (Francesconi). Often at the start of an outbreak, caretakers do not recognize the initial generalized symptoms as EHF and do not take the necessary precautions.

Nosocomial transmission may occur in less developed areas where healthcare facilities have limited equipment, protective clothing and tools such as needles that are reused without being properly sterilized or disinfected. Contaminated needles can cause numerous people to become infected with the virus (Media Centre). In some hospitals, patients may even be treated without any protective ware such as gloves, masks, or gowns (Special Pathogens Branch). The virus can also be transmitted through sexual intercourse. Burial preparations and rituals put family members and the village at risk through exposure to the body and infected secretions (Media Centre). The spread of Reston ebolavirus was more alarming as transmission was airborne and possessed the ability to infect monkeys through the air vents. To stop the virus from potentially leaving the research laboratories, every test monkey was killed (Special Pathogens Branch). Because of the relatively inefficient modes of transmission observed in the EBOV strain infecting humans, outbreaks have been contained in the vicinity of each index case. If other strains acquired effective airborne transmission, the resulting pandemic could truly devastate the human race.

Healthcare workers face typical scenarios consequential to an understaffed center with undertrained workers. During an outbreak, health care workers need materials like masks, gloves, and protective gowns. However, a lack of supplies can increase the chance of workers reusing contaminated supplies that hinders maintaining a sterile environment for the containment of the disease. As the number of infections rise in a community, the people encounter "a mysterious and fearful new scourge" (Bausch, 2008). In many parts of central Africa, there is a cultural belief that the arrival of a disease is associated with sorcery or poisoning and not due to a pathogen. Thus, community compliance remains a conflict to effectively containing the disease. The villages defy healthcare workers and regard isolation wards as a place where one goes to die (Bausch, 2008). The use of government controlled quarantine may be seen as a "death sentence" by many in central Africa and results in the population avoiding health officials or reacting in violence (Hall, 2008). Despite the non-compliance from the community, healthcare workers manage to contain the disease by isolation of the infected patients in a hospital or clinic and maintaining aseptic conditions. There are currently no antivirals or vaccines yet available for an Ebola infection. So, primary control is dependent on meticulous case identification and contact tracing followed by isolation of those infected.

The exact origin and natural reservoir of EBOV remains unknown. There have been several outbreaks of Ebola that have been reported in the world. There have been numerous laboratory tests to try to determine the natural reservoir. Scientists are looking for antibodies and specific nucleotide sequences that code for EBOV in different species of animals. While performing research on filovirus, scientists were able to find antibodies to EBOV as well as viral RNA within the liver and spleen of three species of fruit bats: Epomops franqueti, Hypsignathus monstrosus, and Myoncteris torquata. This suggests that fruit bats may be the reservoirs we are looking for (Leroy, 1598). While no direct link between bat exposure and human disease has been established, the index case of EHF outbreak in 2007 in the Democratic Republic of the Congo was linked to freshly killed fruit bats. The migratory fruit bats were near the outbreak villages and were an important component to the village diet. However, since there are no carriers for the virus and the virus causes an acute infection, scientists are still not completely sure. EBOV continues to be seen in other non-human primates such as chimpanzees, gorillas, and monkeys (Media Centre).

Vaccines and other methods in development are being considered for treatment. Effective treatment for areas such as sub-Saharan Africa must take into consideration the political, legal, and socio-cultural barriers of the affected areas. However, these factors hinder the current vaccine research that is needed to be carried out in these endemic areas of Africa. Potential treatments for these regions have shown some lab studies of poly-and monoclonal antibodies to show mixed results. Even the ribavirin that has proven beneficial in some other hemorrhagic fevers has had no effect on filovirus infections (Bausch, 2008).

EBOV vaccine candidates for humans and apes have shown promise against Ebola viral species Zaire, but three immunizations with a RIBI-adjuvant with an Ebola glycoprotein, an Ebola filamentous protein known as VP40, and a nucleoside protein are needed. Alternatively, another vaccine candidate requires two injections of human parainfluenza vector encoding for the Ebola virus glycoprotein. Both vaccines do not seem feasible for the conditions in Africa since multiple immunizations are required, which may not be properly administered with the limited amount and untrained health workers. Ideal characteristics for an Ebola virus vaccine must consider the nature of the targeted population at risk (Bovendo, 2012). Conversely, a proven treatment for EHF is blocking disseminated intravascular coagulation that is triggered by binding tissue factor to the surface of infected macrophages with the viral circulating factor. This interaction can be blocked with daily injections of recombinant nematode anticoagulant protein C2. In a study of nine macaques infected with Ebola Zaire and treated with the nematode anticoagulant protein C2, the macaques showed a 33% reduction in mortality. A 100-fold drop in peak viremia in the surviving macaques was also observed. Regardless of the potential treatments, EBOV still remains a severely fatal filovirus infection due to the nonspecific antifilovirus thereapies, limited supportive measures, and the lack of compliance and resources from the community (Bausch, 2008).

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