Ebola virus physiological aspects

The identification of the natural reservoir of a virus is of great interest to scientists, because this knowledge gives information as to the geographic range and ecological areas where humans may come in contact with animals or insects that may be the source of the disease. The natural reservoir of Ebola appears to be the fruit bat.

Researchers found evidence that three species of captured fruit bats showed evidence of symptomless infection — that is the bats had Ebola-specific genetic sequences in their bodies or evidence of an immune response to Ebola even though they did not exhibit signs of the disease. Fruit bats live in regions of Africa that include areas where Ebola outbreaks have occurred and are eaten by people in central Africa and may play a key role in transmitting Ebola to great apes and humans.

Bats have been implicated as a reservoir of other viruses that cause deadly diseases including SARS and Marburg.

Infected bats can transmit the virus to monkeys and apes, so humans can become infected while killing or butchering these animals. Cooking destroys the virus, so the risk from infection comes from the preparation of bat or ape meat, not in eating cooked meat.

Humans and animals may also become infected through contact with infected bats or fruit contaminated by infected bat droppings. However, the vast majority of people contract the virus through direct exposure to the body fluids of an infected person.

Ebola is considered an emerging infectious disease. It was first recognized in as the cause of twin outbreaks of disease near the Ebola River in the Democratic Republic of the Congo then known as Zaire and in a region of Sudan. Some people in each country became infected.

The mortality rate was 88 percent in Zaire and 53 percent in Sudan the Zaire subtype is the most deadly. Although the circumstances of the original human infections are not known, the disease spread through close direct contact and as a result of unsafe and unsanitary hospital practices, such as the use of contaminated needles and the lack of sufficient containment measures.

Sporadic and smaller outbreaks have erupted over the succeeding years in the Democratic Republic of the Congo, Gabon, Uganda, and Sudan. An outbreak in the DRC in late August of , that lasted several months, resulted in 66 cases and 49 deaths. As in prior outbreaks, the initial case was traced to the handling of infected bushmeat.

This outbreak in the DRC was caused by a different variant of the Ebola virus that produced the much larger and wide-spread outbreak in the same year in West Africa. The Reston subtype of Ebola virus was first identified in in the United States in monkeys housed in a quarantine facility in Reston, Virginia. At least four humans became infected, but none became ill. Additional outbreaks of the Reston subtype occurred between and in Texas, Pennsylvania, and Italy.

No humans suffered illness in any of these cases. The source of all the Reston subtype outbreaks was traced to a single facility in the Philippines that exported the monkeys. In July of , the discovery of the Reston subtype in domestic pigs in the Philippines was reported. Genetic analysis suggests that the virus has been widely circulating in swine for many years, possibly even before the outbreak in the United States. The virus has been detected in farmers who have had contact with infected pigs, but they have not shown any signs of illness.

Although it took several months for the disease to become recognized as Ebola, it appears that the first victim was a 2-year old boy in a small village in southeastern Guinea who died in December of , followed by the deaths of several members of his family. Although these family members were not tested, their symptoms and the subsequent pattern of virus spread are consistent with the EVD outbreak. The child is thought to have played in a tree that housed Ebola-infected bats, so that he likely came in direct contact with the bats or their droppings.

The virus transmitted by these bats is closely related to the Zaire Ebola virus. Reports came from multiple regions within these countries. Ebola arrived in Nigeria during July when a person who had had contact with an Ebola victim in Liberia traveled by plane to Nigeria and infected several contacts.

In late August, Ebola reached a fifth country when Senegal confirmed its first and, to date, only case. Mali reported its first case in October after a symptomatic young girl traveled from Guinea to Mali and died shortly afterwards, and then an independent small cluster arose a short time later after an elderly man with undiagnosed disease traveled from Guinea to Mali.

The outbreak was quickly contained in Mali, Senegal and Nigeria, but widespread transmission occurred in Liberia, Guinea, and Sierra Leone. The initial transmission of Ebola virus outside of West Africa came to light in early October when a nursing assistant at a hospital in Spain contracted EVD after she had helped care for a missionary who had become infected in Sierra Leone and then flown to Spain. She recovered from EVD, and tests were negative for the presence of the virus following her illness.

Several other people who contracted Ebola in West Africa were treated in hospitals in the United States and in Spain, Germany, the United Kingdom, France, and Norway, but to date no further transmission has occurred. The first diagnosis of Ebola virus infection in the United States was announced on Sept. Prior to traveling to Dallas, Texas, a man had had direct contact with a woman in Liberia who was dying of Ebola.

His symptoms appeared only after he arrived in the United States. While seeking medical attention at a hospital in Dallas, his illness was not immediately recognized as Ebola and he was sent home. He was admitted to the same hospital three days later when his condition worsened, and he died ten days after he was admitted.

A nurse who had contact with this patient during his second hospital stay was confirmed to have EVD on Oct. This was the first known case of transmission within the United States. However, multiple obstacles, such as high frequency side effects, difficulties to manufacture, high cost, low immunogenicity, and lack of a global outreach, interfere with efficacy of EBOV outbreak control [ 24 , 25 ].

This review will provide a comprehensive analysis of all EBOV proteins functions and enlist the protein residues involved. A schematic depiction of the viral life cycle is presented in Figure 2. A simple diagrammatic representation of various steps in the EBOV life cycle. Attachment—EBOV can interact with different host cell receptors, and none of the receptors is indispensable for attachment.

Uptake—Uptake mainly occurs by micropinocytosis, as shown, though other methods such as clathrin-mediated endocytosis and caveolin-mediated endocytosis are also contemplated. Entry—GP1 proteolysis inside endosome enables viral interaction with obligate host receptor cholesterol transporter Niemann-Pick C1 NPC1; shown in red color. Release—After membrane fusion, the viral genome is released in the host cell cytoplasm.

Transcription and Replication—Primary transcription occurs in the host cell cytoplasm followed by a translation. Antigenome is used as a template for synthesis of progeny genomes. Transport—Various proteins are transported near the plasma membrane. None of these receptors are indispensable for EBOV attachment [ 45 , 46 , 47 ], which could include explainability of the virus to target various cell types.

Upon binding to the receptor, EBOV enters the host cells via three mechanisms: a Macropinocytosis [ 48 ], b Clathrin-mediated endocytosis [ 49 , 50 ], and c caveolin-mediated endocytosis [ 51 ].

The internalization mechanism appears related to the shape of the virus. Currently, macropinocytosis is believed to be the primary uptake mechanism [ 52 , 53 , 54 ], while a combination of different mechanisms is also suggested [ 55 , 56 , 57 , 58 ]. The mechanism of proteolysis varies depending on the host cell type [ 59 ] and can be carried out by cathepsin B, cathepsin L [ 60 , 61 ], as well as thermolysin [ 62 ].

This interaction initiates the fusion of viral and host cell membrane, leading to the release of viral RNP into the cytoplasm Figure 2 [ 46 ]. NP encapsidates both, filoviral genome, as well as anti-genome [ 65 ]. Primary transcription and translation take place in the host cell cytoplasm Figure 2. Accumulation of NP and other EBOV proteins results in the formation of inclusion bodies, which serve as additional sites for transcription and replication [ 67 , 68 , 69 ].

Replication is initiated at a promoter region of viral RNA that flanks the transcription initiation sequence of the first EBOV gene [ 70 ]. Importantly, transcription and replication is regulated by the phosphorylated state of VP30 discussed later. The arrangement of EBOV genes is presented at the top, where the symbol indicates the overlapping genes.

Translation of these three transcripts results in three pre-proteins, namely, pre-sGP, pre-GP0, and pre-ssGP, respectively. Transport of RNP employs actin [ 78 , 79 ], while GP is carried to the cell surface via secretory pathway, where it is glycosylated [ 80 ], as well as cleaved into GP1 and GP2 subunits [ 76 ].

It was shown that aa 1— Figure 4 are crucial for NC formation and viral replication [ 87 ]. A recent study indicated the significance of aa in NP oligomerization, viral transcription, and replication [ 91 ]. Interestingly, laboratory data indicate that only point mutations in NP and L are required for virus adaptation to different species [ 93 ]. Interaction of these three motifs with their respective targets is significant to regulate viral transcription. A summary of various critical functions performed by various EBOV proteins and their amino acids involved.

Additionally, various post-translational modifications of NP are documented. Recent studies indicate that NP could interact with host cell proteins to facilitate virus transcription and replication. It was shown that NP recruits host factor carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase in an RNA-independent manner to facilitate EBOV genome transcription and replication [ 98 ]. Additionally, Wendt et al. The critical NP residues discussed above are summarized in Table 2.

It could be suggested that NP is essential for viral replication and transcription. VP35 is crucial for viral transcription and replication [ ] and possesses NTPase and helicase activities, suggesting that it could affect transcription via NTP hydrolysis and NTP-dependent unwinding of RNA helices, respectively [ ].

VP35 also contributes to genome packaging [ ] and nucleocapsid assembly [ 13 , 14 ] as it binds the monomeric state of NP to prevent premature and non-specific encapsidation of viral RNA. VP35 is crucial for host immune response evasion, where host anti-viral defense is inhibited in multiple ways. Phosphorylation of aa regulates VPNP interaction, as well as viral transcription and replication. Further, VP35 aa — Figure 5 can inactivate protein kinase R PKR; an antiviral protein , which enables continuous viral protein synthesis [ ].

Interaction of VP35 with other viral proteins is significant for multiple purposes. VP35 could also function as a non-enzymatic co-factor for the L protein [ ], where several IID constituent residues are critical Table 2 , Figure 5 [ ].

A recent study reported the role of VP35 phosphorylation, especially at aa Figure 5 , in the regulation of VPNP interaction, as well as viral transcription and replication [ ]. Moreover, VP35 is suggested to play a role in NC formation, viral transcription, replication, and genome packaging. Therefore, targeting VP35 might enable the host to mount a more robust immune response and disturb the viral structural integrity.

VP40, the most abundantly expressed protein [ 28 ], is essential for viral assembly and budding [ ]. VP40 aa — Table 2 were reported as critical for VLP production and controlled inhibition of viral transcription, as a mutation in — aa sequence altered these functions [ ].

PTAP makes a complex with tumor susceptibility gene protein tsg [ ], while PPEY binds to ubiquitin ligase, neuronal precursor cell-expressed developmentally downregulated 4 Nedd4 [ ], as well as to ITCH E3 ubiquitin ligase [ ].

The PTAPtsg interaction helps recruit VP40 into lipid raft domains on the plasma membrane [ ], while the PPEY—Nedd4 complex covalently ubiquitinates viral matrix proteins, which is required for virus budding [ ]. These data strongly suggest that L-domains are essential for budding [ ] but limited in viral replication [ ]. Both L-domains are crucial to viral budding. VP40 aa 52—65, 95, —, and are involved in dimerization, while aa — enables VP40—Sec24C interaction. Both the dimerization state and the interaction with Sec24C are significant for proper cellular trafficking of VP VP40 is classified as a transformer protein [ , ], as it could obtain multiple conformational states: dimers, hexamers, filaments and octamers [ ].

VP40 dimerizes in solution with the help of aa 95 and [ ], as well as NTD aa 52—65 and — [ ] Table 2 , Figure 6. Dimerized confirmation is essential for proper trafficking of VP40, where aa — Figure 6 form VPSec24C complex facilitating intracellular transport to the plasma membrane [ 82 ].

Dimers can also assemble into filaments via CTD interactions between two dimers, where aa and Table 2 are shown to be critical. This state is essential for proper matrix assembly and budding [ ].

NTD aa , and [ ] and aa — [ ] Figure 6 are required for proper VP40 localization to the plasma membrane, oligomerization and budding. Additionally, aa , , and facilitate deep penetration of VP40 into the plasma membrane [ ]. The VP40 dimers at the plasma membrane are then oligomerized into linear VP40 hexamers [ , ]. Both deep penetration and hexamer formation are critical to viral assembly and budding [ , ].

A recent study highlighted the significance of aa for effective VP40 localization to the plasma membrane, oligomerization and VLP formation [ ]. In addition to dimers, filaments, and hexamers, VP40 can form an octameric ring configuration where NTD plays the leading role [ ].

The latter is implicated in the negative regulation of transcription [ ]. These data indicate that the main function of VP40 is in viral assembly and budding Table 2 , Figure 6. Therefore, targeting critical VP40 aa might help suppress viral spread after infection by hindering the budding process. Additionally, it is suggested to play a role in viral transcription inhibition and interaction with the host cell plasma membrane.

As the only EBOV protein present on the viral surface, GP is responsible for pathogenic differences of ebolaviruses [ ]. In other studies, it was shown that aa , , , [ ], and — [ ] Table 2 provide protein stability, while aa 55, 57, 63, and 64 are involved in membrane fusion-mediated conformational changes [ ].

GP has a cathepsin cleavage site at aa — Table 2 , Figure 7 [ , ], which is proteolyzed inside the endosome, a step critical for viral infection [ 60 , 61 ]. GP is post-translationally cleaved by furin at aa residue Figure 7 , resulting in GP1 and GP2 subunits linked by disulfide bonds [ 31 , 75 , 76 ].

These heterodimers form trimeric viral peplomer [ 31 ]. GP aa 54— form the receptor-binding domain RBD or receptor binding site RBS responsible for attachment to host cell-surface receptors. Cathepsin cleavage site is present in aa —, and proteolysis via cathepsins is significant for viral infectivity. The immunosuppressive motif aa — plays a role in bystander lymphocyte apoptosis and cytokine dysregulation.

GP1 mediates attachment to host cells using the receptor-binding site RBS located at aa 54— Figure 7 [ ]. Studies have identified multiple aa Table 2 as critical for viral entry [ , , , , , ]. Among these, aa 64, 95 [ ] and , , [ ] are involved in direct contact with host cell receptors while aa 43, 54, 56, 60, 61 and 79 contribute to post-binding steps of viral entry [ ].

GP2 contributes to the fusion of viral and host cell membranes [ ]. An internal fusion loop at aa — position Figure 7 [ ] consists of hydrophobic residues Table 2 inserted into the target cell membrane [ ]. An immunosuppressive motif aa —; Figure 7 located near the C-terminal [ 29 , 31 ] can cause lymphocyte apoptosis, as well as cytokine dysregulation during EVD [ ].

Post-translational N-linked glycosylation of GP results in a thick coating of oligosaccharides, protecting viral GP against host humoral immune response [ ] and promoting protein expression and function [ ].

In total, 15 N-linked and 80 O-linked glycosylation sites have been identified in GP1 [ 32 , ]. GP2 has 2 N-linked glycosylation sites aa and ; Table 2 [ 75 ] critical for GP processing, oligomerization and confirmation [ ].

Six N-glycosylation sites aa 40, , , , , and [ ] and one C-mannosylation site aa [ ] have been identified in sGP. A potential contribution of sGP in viral dissemination was suggested by Bradley et al. It was also shown that sGP contributes to host immune evasion by acting as a decoy for anti-GP antibodies [ ].

In a recent study, detection of serum sGP was suggested as a biomarker for Ebola virus disease EVD diagnosis as large quantities of this protein are found in blood at the early stages of the disease [ ]. It is a O-glycosylated, sialylated peptide [ 30 ] rich in cationic and aromatic residues [ ]. It can inhibit viral entry into filovirus-permissive cells, preventing superinfection [ , ].

In , Gallaher et al. It is also believed that shed GP helps to reduce the cellular cytotoxicity caused by GP [ ]. Additionally, shed GP activates non-infected dendritic cells and macrophages [ ], leading to massive cytokine production and increased vascular permeability [ ]. It is secreted as a N-glycosylated homodimer formed by intermolecular disulfide bond at aa 53 [ 10 ].

Function of ssGP still remains unknown [ ]. To summarize, GP, as the only protein on the viral surface, is responsible for viral entry, i. GP—NPC1 interaction is an indispensable step for viral infection, and, therefore, targeting GP shall hinder the viral infection. Therefore, targeting various GP gene products might be beneficial in the development of an effective vaccine. VP30 is a structural, hexameric phosphoprotein composed of three dimers [ 33 , ].

Dimers are formed by aa —, while aa 94— Figure 8 are required to produce hexameric form [ , ]. VP30 aa 27—40 Figure 8 form a disordered, non-hydrophobic, arginine-rich region interacting with viral RNA [ ]. VP30 is indispensable for RNA transcription initiation [ ]. Interestingly, mutations at aa , , and render VP30 incapable of transcription initiation, suggesting their importance in this process [ ].

The NP gene transcription starts signal forms a stem-loop like secondary structure, essential for VPdependent transcription initiation [ ]. The VP30 aa — Table 2 , Figure 8 are responsible for VP30—NP complex formation [ 96 , 97 , ], and a threshold level of interaction is required for optimal viral transcription, below and beyond which transcriptional activity is flawed [ 96 ].

Further, VP30 role in regulating viral RNA transcription requires a zinc-binding site located at aa 68—95 Figure 8 [ ]. VP30 phosphorylation mainly occurs at serine aa 29—31, 42, 44, and 46 and threonine aa 52, , and residues Figure 8 [ 33 , ]. Low or un-phosphorylated VP30 seems responsible for transcription initiation of all seven genes in the EBOV genome [ , ].

Whether low or un-phosphorylated VP30 is required as a transcription factor depends on the virus replication stage. Amongst the phosphorylation sites, aa 29 seems to be the most critical as it can solely execute all VP30 transcription functions [ ].

Complete VP30 phosphorylation at all serine residues between aa 29—46 abrogates transcription initiation function [ ]. The impact of phosphorylation on VPNP interaction was extensively debated over the past two decades [ 33 , , ]. The latest consensus states that phosphorylation leads to a more robust interaction with NP which allows VP30 to be associated with NC and enter newly synthesized virus particles, wherein the un-phosphorylated VP30 can initiate transcription [ , ].

Overall, it is accepted that the phosphorylation state of VP30 is dynamic and modulated by the virus to achieve an intricate balance between transcription and replication processes, which happen simultaneously during the EBOV life cycle [ , ].

The above discussion suggests that VP30 chiefly plays a role in viral transcription initiation via its zinc-binding, NP interaction and phosphorylation characteristics Table 2 , Figure 8. Abrogating this function shall hinder the production of multiple RNA copies.

Therefore, VP30 is a plausible candidate for therapeutic and vaccine development studies targeting primary transcription in the host cell cytoplasm. VP24 makes up approximately 7. This structural change also signals the end of replication and the beginning of the egress phase [ , ]. Like VP35, VP24 inhibits host immune response using several mechanisms [ ].

Additionally, the role of aa 96—98 and — Figure 9 indirect interaction of VP24 with un-phosphorylated STAT1 was reported [ , ]. Further, it was reported that oxidative stress effects the VP24 modulation of the host response, facilitating recovery of infected cells from stress [ ].

VP24 also seems critical to viral replication and is involved in budding viral initiation. Therefore, targeting these residues Table 2 during vaccine development may hinder viral replication. L protein aa 1— Figure 10 are involved in L-VP35 interaction, which happens in a non-competitive manner and does not require L homo-oligomerization [ ].

The L-VP35 binding enables re-localization of L into viral inclusion bodies. L protein is essential for virus replication, yet little is known about its other functions, mainly due to its large size and lack of specific antibodies [ , ]. It also regulates cap methylation aa , , , , , and and internal methylation aa , , , , , , , and activities of methyltransferase domain [ ].

It is imperative to understand proteins functions with respect to the EBOV life cycle and pathogenesis to identify practical and specific protein therapeutic targets.

This review summarizes data on aa residues of EBOV proteins involved in essential functions, such as viral entry, host immune evasion, replication, transcription, and budding. Multiple proteins and aa sites were highlighted in our review, which have a high potential for vaccine development. For instance, NC formation and viral replication could be hindered by collectively targeting NP aa — and VP24 aa — Replication and its regulation could also be affected by targeting VP35 aa and L aa — Viral transcription could be affected by targeting NP aa —, NP aa —, and VP30 aa —, while transcription regulation can be blocked by collectively targeting NP aa —, VP35 aa 20—48, and VP30 aa 29— Moreover, targeting NP aa stretch — might disable multiple NP-host-protein interactions significant for transcription and regulation.

Viral ingress may be blocked by targeting GP aa 54— as it affects GP stability, interaction with obligate host receptor NPC1 and membrane-fusion mediated conformational changes. This could be prevented by targeting specific regions of these proteins, such as VP30 aa — and VP24 aa — This will be effective in preventing viral entry, as well as in curbing host immune evasion.

Survivors exhibited more significant IgM responses, clearance of viral antigen, and sustained T-cell cytokine responses, as indicated by high levels of T-cell-related mRNA in the peripheral blood.

During infection, there is evidence that both host and viral proteins contribute to the pathogenesis of Ebola virus. Moreover, in vitro experiments demonstrated that tumor necrosis factor released from filovirus-infected monocytes and macrophages increased the permeability of cultured human endothelial cell monolayers Whether the effects of cytokines are protective or damaging may depend not only on the cytokine profile but also may represent a delicate balance influenced by the route and titer of incoming virus as well as factors specific to the individual host immune response.

Several animal models have been developed to study the pathogenesis of Ebola virus infection and to assess the efficacy of various vaccine approaches. Guinea pigs and nonhuman primates represent the primary animal models for vaccine development because the progression and pathogenesis most closely resemble those of the human disease 10 , 46 , A murine model was later developed by serial passage of virus in mice 7.

Though the model allows the use of knockout and inbred strains to evaluate genetic determinants of disease, it is considered less predictive of human disease because it relies on a serially passaged, attenuated virus. While symptoms and time course of disease in guinea pigs parallel those in humans, nonhuman primate infection is considered the most predictive and useful for vaccine development Live attenuated viruses and recombinant proteins have been used successfully in a variety of vaccines, but the safety and immunogenicity of gene-based vaccines have proven increasingly attractive.

Among the gene-based approaches, naked plasmid DNA has been used successfully in animal models to direct the synthesis of immunogens within the host cells and has proven helpful in a variety of infectious diseases reviewed in references 11 and Genetic immunization with plasmid DNA was developed in the guinea pig and was the first successful vaccine for Ebola virus In this model, NP elicited a primarily humoral response and was less efficacious, while sGP and GP elicited T-cell proliferative and cytotoxic responses as well as a humoral response.

Protection against lethal challenge was conferred by each of these immunogens when animals were infected within 1 month of the last immunization, but only GP or sGP provided long-lasting protection. The degree of protection correlated with antibody titer and antigen-specific T-cell responses. Subsequent studies of NP and GP plasmids conferred protective immunity in mice 39 , but it is uncertain whether the attenuated murine virus is more sensitive to neutralization than the wild-type virus.

Thus, the relative potency of NP, or its requirement as an immunogen for providing long-term protection, remains uncertain. While DNA vaccines have been highly effective in rodents, their efficacy in nonhuman primates or humans has been less impressive. Priming-boosting immunization protocols that use DNA immunization followed by boosting with poxvirus vectors carrying the genes for pathogen proteins have yielded dramatically enhanced immune responses in animal studies, with fold or greater increases in antibody titer from the booster A different priming-boosting strategy using replication-defective adenovirus for an Ebola virus vaccine was tested in cynomolgus macaques This study demonstrated the superior immunologic efficacy of this priming-boosting combination for both cellular and humoral responses.

These animals displayed complete immune protection against a lethal challenge of virus, providing the first demonstration of an Ebola virus vaccine approach that protects primates against infection.

Recently, an accelerated vaccination has been developed that confers protection against a lethal virus challenge in nonhuman primates after a single immunization 36a.

If this vaccine works similarly in humans, it may be useful in the containment of acute outbreaks by ring vaccination. In summary, an understanding of the mechanisms underlying Ebola virus-induced cytopathic effects has facilitated the process of vaccine and antiviral therapy development, which has in turn provided new information about pathogenesis and the immune response.

Ebola virus does not exhibit the high degree of variability that other enveloped viruses may employ to evade host immunity, but Ebola virus GP alters target-cell function and exemplifies a novel strategy for immune evasion that may have arisen through the evolution of Ebola virus with its natural host.

The cytotoxic effects of GP on macrophage and endothelial cell function disrupt inflammatory cell function and the integrity of the vasculature. In addition, by altering the cell surface expression of adhesion proteins and immune recognition molecules, Ebola virus may disrupt processes critical to immune activation and cytolytic-T-cell function.

These phenomena likely account for the dysregulation of the inflammatory response and the vascular dysfunction characteristic of lethal Ebola virus infection, providing a rationale for focusing on GP as a target for a preventative vaccine and providing leads for other clinical interventions.

National Center for Biotechnology Information , U. Journal List J Virol v. J Virol. Gary J. Author information Copyright and License information Disclaimer.

Phone: Fax: E-mail: vog. This article has been cited by other articles in PMC. Open in a separate window. Alvarez, C. Lasala, J. Carrillo, A. Corbi, and R. Baize, S. Leroy, M. Georges-Courbot, M. Capron, J.

Lansoud-Soukate, P. Debre, S. Fisher-Hoch, J. McCormick, and A. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients.

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Drenckhahn, and H. Nichol, H. Infected humans can transmit the virus through contact with bodily fluids, including saliva, blood, urine, feces, sweat, breast milk, semen, or fomites. Interestingly, the Ebola virus can survive in semen for up to 21 days after the patient has recovered.

To date, there is conflicting information on whether vaginal secretions harbor or spread the Ebola virus. Once infected, the virus will incubate within the host during an asymptomatic, non-contagious period, usually lasts between several days to a few weeks.

An infected person exhibiting signs and symptoms resembling a typical viral illness is considered contagious. The virus enters the new host through mucosal membranes or broken skin. Note the mucosal membrane does not need to be damaged for the virus to enter the host. The virus can survive outside the human body for an unknown amount of time. Most often, the bedding, clothes, medical utensils utilized in patients are all burned or disposed of as medical waste to avoid contamination and the risk of spreading the virus.

The Ebola virus was originally discovered in , considered a rare, exotic disease mostly studied in highly classified laboratories.

Since its discovery, over 20 outbreaks have occurred since ; many outbreaks were confined to rural areas in Sudan, Democratic Republic of Congo, Gabon, Republic of the Congo, and Uganda.

Endemic outbreaks of the Ebola virus, most commonly Zaire and Sudan ebolavirus , are attributed to eating contaminated monkey meat. The epidemic spread is usually due to transmission to family members, then community members, and funeral practices.

The most recent outbreak is considered ongoing since June 1, , in the Democratic Republic of the Congo. This complex epidemic crippled healthcare systems in some countries and shed light on the lack of preparedness for epidemics. Most reported cases outside of Africa were in healthcare workers providing aid in regions with an active outbreak, with strict travel restrictions and effective quarantine strategies, only a few travelers were infected due to direct human contact.

The Ebola virus is only infectious when a person is experiencing prodromal symptoms such as fever, chills, nausea, vomiting, or when people come in contact with infected dead bodies. Once the virus infects the host, there is an incubation period of 2 to 21 days. From the onset of symptoms, death can occur very quickly, often within six days. Patients who recover have developed specific antibodies to the Ebola virus. On a molecular level, the presence of the virus in the blood causes the direct release of cytokines, which activates acute phase reactants causing cell damage.

The hemorrhagic aspect is more complex and involves disruption of the coagulation cascade through platelet aggregation, which sequesters platelets causing increased clots and clotting simultaneously, respectively. The virus replicates after it penetrates the host cell membrane by binding with glycoproteins spikes and clathrin-mediated endocytosis. Once inside the cell, the virus releases its nucleocapsid into the host cell cytoplasm, where it replicates. Transcription and translation of the viral RNA into viral proteins is initiated by VP30 activating the start gene.

Phosphorylation of VP30 by transcribed viral proteins turns of VP30, in this, VP30 seems to be a regulatory protein, and pharmaceutical research is underway to specifically target VP Currently, this process is not fully understood.

Persons or healthcare workers present with sudden fever, nausea, abdominal pain, vomiting, diarrhea, malaise, myalgias, bleeding from mucosal membranes, skin, eyes, nose, ears. Especially those who traveled to or came in close contact with anyone who has traveled to endemic countries with known or active outbreaks of Ebola virus within the last three weeks got infected. On physical exam, the patient may present with prodromal symptoms and stable or advanced illness and in shock.

The primary and most important survey will be to assess the patient and acquire a good set of vital signs, including temperature, blood pressure, heart rate, oxygen saturation, respiration rate. The cornerstone of management and treatment for patients infected with the Ebola virus and exhibiting symptoms of Ebola virus disease is supportive care.

Repeating fluid loss with IV administration of fluids and electrolytes, controlling temperature with antipyretics.

In addition to supportive care, extensive, emergency research during the last Ebola virus outbreak showed promising results. These studies focused on treatment therapies including the use of convalescent plasma, monoclonal antibodies, anti-viral drugs such as remdesivir. Further prevention of spread, through imposing international travel bans and exit screenings upon departure from countries with active Ebola outbreaks is a critical non-medical intervention.

Ebola virus disease should be differentiated from other causes of hemorrhagic fever and common viral illnesses presenting with similar prodromal symptoms and gastrointestinal symptoms. The rate of recovery depends on early intervention and access to adequate healthcare with the administration of continuous supportive care and close-interval patient reassessment.