Symptoms of ebola virus infection

This increases permeability of the blood vessels -- leading to blood leaking out of the vessels. Even people who don't show hemorrhagic symptoms will experience this leaking of blood from the vessels -- which can eventually lead to shock and, ultimately, death.

The Ebola virus is also a master of evading the body's natural defenses : It blocks the signaling to cells called neutrophils, which are white blood cells that are in charge of raising the alarm for the immune system to come and attack. In fact, Ebola will infect immune cells and travel in those cells to other parts of the body -- including the liver, kidney, spleen and brain.

Each time one of the cells is infected with the Ebola virus and bursts, spilling out its contents, the damage and presence of the virus particles activates molecules called cytokines. In a healthy body, these cytokines are responsible for provoking an inflammatory response so that the body knows it's being attacked. But in the case of an Ebola patient, "it's such an overwhelming release [of cytokines], that's what's causing the flu-like symptoms" that are the first sign of Ebola, Bhadelia said.

Ebola generally starts with flu-like symptoms. Though it's known for the extreme hemorrhagic symptoms -- the bleeding out of the eyes, etc. The flu-like symptoms typically occur in the first stages of the illness, before the person gets sicker and starts to experience more severe symptoms such as vomiting, diarrhea and low blood pressure. The extreme bleeding occurs toward the end of the illness.

People who die from infection with Ebola virus usually end up dying from multi-organ failure and shock. It largely has to do with two factors. The first is the person's health in general -- his or her immune system and ability to bounce back from a viral infection. The second is the type of exposure he or she got. Recovery may be more likely if it wasn't a severe exposure -- meaning, perhaps they were exposed to someone who was only early on in the illness, and the amount of virus in the bodily fluids was not yet that high, Bhadelia said.

In addition, what is known about Ebola is that it requires a known marker that aids in bringing the virus from the surface of the cells into the cells. Researchers have found in a laboratory setting that some people's cell lines actually lack this marker, or it may be mutated somehow, so that the Ebola can't get into the cells. Matrix space between the virion envelope and central nucleocapsid houses viral matrix proteins, VP40 and VP VP40 mediates budding as well as viral particle release while VP24, a minor matrix protein, participates in nucleocapsid formation and assembly, also regulating viral transcription and replication.

In the centre of the virion, a nucleocapsid is present which is composed of a series of viral proteins attached to a linear non segmented, single negative stranded RNA genome. Four nucleocapsid proteins: nucleoprotein NP, RNA polymerase L, polymerase cofactor VP 35 and transcription factor VP 30, are important for replication and transcription of viral genome [ 12 ].

Life cycle of Ebola virus begins with the binding and attachment of virion to specific surface receptors on target cell membrane mediated via glycoprotein subunits.

The virion envelope subsequently fuses with the cellular membrane of host cells and the virus nucleocapsid is released into the cytosol resulting in viral uptake. The internalized nucleocapsid serves as a template for viral transcription and replication resulting in copying into full-length, positive-strand RNA antigenomes.

These antigenomes serve as templates for transcription into negative-strand virus progeny genome copies. Newly synthesized structural proteins and genomes then self-assemble and accumulate under cell membrane, sites from where the virus is released. When budding off from the cell, virions gain envelope from the cellular membrane they bud from.

These mature progeny particles infect other cells to repeat virion cycle; in this manner replicating at an extraordinarily high rate and exploiting cellular machinery, by overpowering protein synthesis apparatus of infected cells as well as host immune defenses [ 10 - 12 ]. The common host targets in Ebola virus infection are primary host targets which include monocytes, macrophages and dendritic cells; organ targets which include liver and adrenals and secondary targets which include fibroblasts and endothelial cells.

Transmembrane GP compared to sGP forms a trimeric complex that binds the virus preferentially in the earlier stages of infection to cells of mononuclear phagocytic system i. Early target attack combined with additional dendritic cell infection influences the innate and adaptive immune responses of the host resulting in rapid and extensive dissemination of the virus even upto levels of Widespread distribution of virus to various parts of the body is thus facilitated by blood flow containing free virus particles and infected monocytes, free virions and infected dendritic cells in lymphatic flow and cell to cell spread via cellular protrusions.

Migration of infected monocytes into connective tissue infects fibroblasts promoting further spread to surrounding cells by cellular protrusions. A peculiar feature of fatal EVD cases is the minimal presence of inflammatory cells — neutrophils, lymphocytes and monocytes around viral infected cells contrary to non fatal cases where leukocyte concentration around infected cells may restrict viral dissemination [ 12 ]. As infection progresses, virus infects endothelial cells lining the inner surface of blood vessels resulting in vascular dysfunction and loss of vascular integrity precipitating haemorrhagic symptoms.

Ultimately in advancing infections, infected macrophages, dendritic cells, endothelial cells and hepatocytes undergo non apoptotic cell death and necrosis. Secreted glycoprotein sGP does not participate in viral replication rather is secreted from infected cells. It forms a dimeric protein that interacts with neutrophils by mediating neutrophil binding either directly or indirectly through CD16b [10].

Neutrophil binding interferes with the signaling of neutrophils and aids the virus to evade host immune system by inhibiting early steps of neutrophil activation which ordinarily supports viral clearance. Further, neutrophils serve as carriers to disseminate virus throughout the entire body to places such as lymph nodes, liver, lungs, and spleen [ 13 , 14 ].

Thus, sGP alters immune response by inhibiting activation of neutrophils, while transmembrane GP may contribute to haemorrhagic fever symptoms by targeting virus to cells of the reticulo endothelial network and the lining of blood vessels [ 10 ]. The exact natural reservoir host for Ebola virus still remains uncertain.

Birds, arthropods and plants are considered to be the possible reservoirs of Ebola virus but it is not yet conclusively established whether these are primary reservoirs or intermediate reservoirs getting infected from the primary reservoirs. Bats appear to be the most likely reservoir as there are hardly any clinical signs that can be found in them. In a recently conducted experiment that included 24 plant species and 19 vertebrates inoculated with Ebola virus, results showed bats to be infected, carrying and spreading the disease [ 15 ].

Specifically, the fruit bat species such as Epomops franqueti, Hypsignathus monstrosus, and Myonycteris torquata were found to carry the virus without showing any symptoms of the disease. Of the five known subtypes of Ebola virus, four types are known to dwell in an animal host which is native to Africa.

Figure showing transmission of Ebola virus. Contact with infected bats, duikers and non human primates can spread infection from animals to humans, following which human-human transmission can occur.

Spread of Ebola virus is known to occur through contact with infected animals or humans; most likely, through direct contact of broken skin or unprotected mucous membranes with virus-containing body fluids. Animal to human transmission takes place through contact with meat or body fluids of the infected animal.

EVD shows no sexual predilection, but men and women differ with respect to the manner in which the direct exposure can occur. Infection amongst humans can transmit through physical contact with infected skin or bodily fluids such as blood, feces or vomit.

Ebola virus has additionally been detected in saliva, mucus, urine, semen and breast milk. Male survivors may be able to transmit the infection via semen for nearly two months. Routes of entry are open wounds, abrasions and cuts. In saliva, it has been found most frequently during the severe stage of illness. Infected patients are not considered communicable prior to onset of symptoms i.

Risk of transmission is also very low during the early onset of symptoms. However, there is an increase in communicability with each subsequent stage of illness with maximum chances of infection in later stages.

Cases continue to remain communicable as long as blood and body fluid secretions contain the virus i. Ebola virus does not show any airborne transmission, but may inadvertently spread via droplets that are coughed or sneezed from a sick person. Subsequently, these droplets may enter the eyes, nose, or mouth of another person who is less than two meters away. Strategies should therefore be undertaken to reduce aerosol generation in aerosol generating medical procedures.

Due to this potential characteristic of the virus, it has also been classified as a highly potential agent of bioterrorism. Indirect transmission from surfaces or objects previously contaminated by blood or bodily fluids is a possibility but risk of transmission by this method is low. Medical workers are at a high risk of contracting the disease particularly when appropriate personal protective gear is not available or improperly used.

Hospital acquired infections are likely when needles are reused and adequate containment measures are not practiced. It is therefore advised to properly handle and dispose contaminated medical equipment like syringes and needles. Ebola virus disease EVD is often deadly in humans and usually runs its course from 14 to 21 days. Its incubation period is typically 8 to 10 days, but can vary between 2 and 21 days. Infection initially presents with sudden nonspecific influenza-like symptoms characterized by fever, fatigue, headaches, joint, muscle and abdominal pain.

Besides these, gastrointestinal symptoms like abdominal discomfort, nausea, vomiting, diarrhea and loss of appetite are also frequently seen. Other less common symptoms include: sore throat, chest pain, hiccups, dyspnoea and difficulty in swallowing.

In the later stages of illness, patients may suffer from profuse vomiting and diarrhea which unchecked could result in severe volume depletion, electrolyte imbalance and shock. Symptoms of EVD before progression into bleeding phase are very similar to those of malaria, dengue fever or other tropical fevers and hence warrant close monitoring throughout [ 16 ]. Bleeding phase typically sets in 5 to 7 days after the onset of first symptoms.

In advancing stage of illness, the virus starts targeting microvascular endothelial cells resulting in loss of vascular integrity and leakage of blood [ 10 ]. Subsequent internal and subcutaneous bleeding manifests as haemorrhages under the skin seen as petechiae, purpura, ecchymoses and haemotomas particularly around needle injection or puncture sites. Bleeding from mucous membranes like gums, nose, gastrointestinal tract and vagina have also been reported.

Liver damage associated with massive viremia leads to disseminated intravascular coagulopathy. Infected patients sometimes exhibit symptoms of circulatory system involvement, including impaired blood clotting [ 17 ]. On the whole, bleeding is generally indicative of poor prognosis as hypotensive shock resulting from blood loss due to diffuse bleeding often results in death.

In the event of non recovery of an infected person, multiple organ failure contributing to death can be expected within 7 to 16 days usually between days 8 and 9 after first symptoms [ 18 ]. Usually, if the patient is able to survive one week post onset of symptoms, recovery is rapid and complete. If EVD is suspected, thorough medical history including travel and work history as well as any exposure to wildlife in recent past is important to investigate. Laboratory tests that may be indicative include basic blood tests — Complete blood count CBC with differential, liver enzymes, bilirubin, creatinine levels, blood urea nitrogen BUN and pH.

Isolating virus by tissue culture to be performed only in high-containment laboratories , detecting viral RNA by polymerase chain reaction PCR and antigen detection by enzyme-linked immunosorbent assay ELISA are effective early and in those who have died from the disease. Serologic testing for demonstrating immunoglobulin M IgM and immunoglobulin G IgG antibodies against the virus is effective late in the disease and in those who recover [ 18 ].

Differential diagnosis includes VHFs such as Crimean-Congo haemorrhagic fever, Marburg haemorrhagic fever and others, malaria, typhoid, shigellosis, rickettsial diseases like typhus, cholera, gram- negative septicemia, leptospirosis, borreliosis, scrub typhus, plague, trypanosomiasis, visceral leishmaniasis, measles, haemorrhagic smallpox, and fulminant viral hepatitis. Hereditary haemorrhagic telangiectasia, warfarin poisoning and Kawasaki disease should also be considered in differential diagnosis [ 19 ].

In addition to precipitating exaggerated non protective systemic inflammatory responses and impairing vascular and coagulation systems, Ebola virus infection is also known to result in profound immune suppression giving little opportunity for development of natural immunity.

Ebola virus acts both directly or indirectly to disable antigen-specific immune responses. Generally, lymphocytes in an infected individual continue to remain uninfected and are spared of viral replication, possibly because of lack of specific surface receptors essential for binding; but undergo apoptosis and subsequent clearing by surrounding macrophages [ 12 ]. Apoptosis of lymphocytes may be attributed to various intrinsic and extrinsic pathways, one of them being dysregulated dendritic cells and macrophages.

Dendritic cells, which are primarily responsible for initiation of adaptive immune responses, are a major site where the virus replicates. Infected cells fail to undergo maturation and are unable to present antigens to naive lymphocytes.

It is hypothesized that resultant depletion of lymphocytes due to extensive lymphocyte apoptosis arrests adaptive immunity and overwhelms viral pathogenesis.

However, ensuing experiments lately have indicated that lymphocyte apoptosis is a byproduct of fatal infection and is not required for pathogenesis. Protection offered by antibody transfer is mainly by 1 restricting viral replication and 2 some replication may be observed but it blunts the infection such that T cell and innate immunity are capable of resolving the infection.

In animal models such as guinea pigs, immune serum containing high titers of neutralizing antibodies has known to confer protection in Ebola virus infections when administered prior to, rather than after, Ebola virus challenge [ 21 ]. Passive transfer of antibodies immediately post exposure in monkeys has shown to delay the onset of viremia and clinical signs but has not shown to alter their overall survival [ 22 ].

Human monoclonal neutralizing antibodies when used in guinea pigs showed good efficacy in post exposure prophylaxis by reducing viremia and increasing survival rate where as when using the same antibodies in macaques, they failed to protect the animals against lethal ZEBOV challenge [ 23 , 24 ]. Transfer of immune sera with antibodies specific to viral proteins other than glycoproteins has shown fewer efficacies. In humans, EVD progress is so rapid that an infected individual may die even before antibodies are detected.

However, in patients recovering from Ebola virus infection, antibody titers against Ebola virus GPs are readily demonstrable but their titers in serum may not be sufficient enough to provide any protection against infection or render neutralizing activity invitro, warranting use of immunoglobulin preparations that contain more concentrated neutralizing antibodies [23].

More recently, selected monoclonal antibodies isolated from the bone marrow of recovered patients have shown to effectively neutralize Ebola virus replication in vitro [ 10 , 25 ]. Collectively, these results indicate that there is a complex interaction between EBOV and host immune system. Immune responses are likely to vary depending on virus strain, type of animal model and type of vaccine. Also, antibodies alone may not confer complete protection in filovirus infection rather concomitant cellular immunity is integral to achieving protection.

On comparing immune parameters, significant differences in immune responses have been noted in fatal and non fatal cases of Ebola infection. Baize et al. They found that despite similar viral antigen loads being present in survivors and nonsurvivors, immune responses were different in both groups.

Low levels of T cell cytokine RNA levels in peripheral blood are indicative of lack of development of adaptive immunity in individuals just preceding death. Survival on the other hand is dependent on initial or innate immune responses to infection. Despite ongoing research in this field, none of the anti viral agents or vaccines for Ebola virus are currently approved for human use by the regulatory bodies.

Currently available vaccines are still experimental and require full testing for safety and efficacy in humans. Promising vaccines undergoing clinical trials are those that are derived from adenoviruses, Vesicular Stomatitis Indiana Virus VSIV or filovirus-like particles VLPs as these are well known to render protection in nonhuman primates [ 28 , 29 ]. In , a vaccine using an adenoviral ADV vector carrying the Ebola spike protein was tested on crab-eating macaques.

After twenty-eight days, when challenged with the virus, animals remained resistant [ 30 ]. A single shot blended vaccine based on attenuated recombinant Vesicular Stomatitis Virus VSV vector carrying equal parts of vaccine vectors — Zaire ebola virus glycoprotein, Sudan ebola virus glycoprotein and Marburg glycoprotein, when used in nonhuman primates was able to confer protection against three species of Ebola virus and Marburg virus thereafter opening clinical trials in humans [ 31 ].

Gene-based vaccines owing to their safety and immunogenicity have proved increasingly attractive. Find this interesting? Share it! Facebook Twitter. By clicking "Continue" or continuing to use our site, you acknowledge that you have read and understood our Cookie Policy, Privacy Policy and Terms of Use.

Ebola Virus Species. Zaire ebolavirus. Active reported cases and fatality rates are ongoing As at 21 May 51 reported cases — suspected, probable and confirmed 27 fatalities. Sierra Leone Liberia Guinea. DRC Uganda Uganda. Bundibugyo ebolavirus Sudan ebolavirus Sudan ebolavirus.

Sudan ebolavirus. Uganda DRC. Bundibugyo ebolavirus Zaire ebolavirus. DRC Sudan England laboratory accident. Zaire ebolavirus Sudan ebolavirus Sudan ebolavirus. Year of Outbreak.

Outbreak Locations. Philippines associated with pig farming. Cases reported: 6.