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Viral Hemorrhagic Fevers. The Filoviruses Steve Vivian Jenn. Live Footage. Ebola Virus Outbreak. Viral Hemorrhagic Fevers. Severe multi-system syndrome (multiple organs affected). Vascular system is damaged and body loses the ability to regulate itself. Accompanied by hemorrhaging.

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viral hemorrhagic fevers

Viral Hemorrhagic Fevers

The Filoviruses

Steve

Vivian

Jenn

live footage
Live Footage

Ebola Virus Outbreak

viral hemorrhagic fevers3
Viral Hemorrhagic Fevers
  • Severe multi-system syndrome (multiple organs affected).
  • Vascular system is damaged and body loses the ability to regulate itself.
  • Accompanied by hemorrhaging.
  • Many VHF viruses cause life threatening diseases
  • Most have no established treatment or cure.
vhf caused by viruses of 4 families
VHF Caused by Viruses of 4 Families
  • Arenaviruses
  • Filoviruses (Ebola and Marburg)
    • Work with filovirus species requires Biosafety Level 4 (BSL-4) “space suit” containment (HIV requires BSL-2 “space suit” containment).
  • Bunyaviruses
  • Flaviviruses
slide5
Features of these Viruses
    • RNA Viruses, covered in lipid coating
    • Humans are not natural reservoir, but can transmit virus
    • Viruses are restricted to areas of their host species
marburg
Marburg
  • Caused by a zoonotic virus of the filovirus family.
  • Mortality Rate 23-25%
slide7
First recognized in 1967 when simultaneous outbreaks occurred in Marburg and Frankfurt, Germany, and in Belgrade, Yugoslavia.
      • 37 people became ill. The ill were mostly laboratory workers and medical personnel.
      • Original people who became ill had been exposed to the tissues of African green monkeys, which were imported from Uganda for research.
slide8
Location:
    • The area to which the virus is native is unknown, but it is believed to include parts of Uganda, Western Kenya, and Zimbabwe.
  • Transmission
    • The animal host to the Marburg Virus is unknown, and so is the way that the animal transmits the disease to humans.
    • People who have been exposed to infected monkeys or their body fluids have become infected in the past.
slide9
Transmission (continued)
    • The disease is easily transmitted between humans. Direct contact with an infected person, or exposure to their body fluids, are both ways by which the disease is thought to be transmitted.
ebola
Ebola
  • Believed to be caused by a zoonotic member of the filovirus family.
      • Believed to be carried by an animal host that is native to Africa.
  • Named after a river in the Democratic Republic of Congo in Africa (formerly Zaire) where first outbreak occurred in 1976.
  • First Ebola outbreak in Zaire (1976)- 318 Human cases, 88% of those people died of the disease.
great plague of athens 529 b c
Great Plague of Athens529 B.C.
  • Thucydides wrote about a disease with symptoms that are very similar to Ebola, including:
    • High Fever, Vomiting, Chest Pain, Diarrhea, fetid breath and a bumpy red rash.
slide12
4 Types of Ebola Virus
      • Ebola-Zaire
      • Ebola-Sudan
      • Ebola-Ivory Coast
      • Ebola Reston

All of these strains have been known to cause disease in humans, except for Ebola-Reston, which has only caused disease in Non-Human Primates.

Electron Micrograph of Ebola Virus

slide13
Location:
    • The Ebola Virus has been reported in the Democratic Republic of Congo, Gabon, Sudan, the Ivory Coast, and Uganda.

Map of Ebola Outbreaks in Africa

slide14
Ebola-Reston outbreak at primate research facility in Virginia. Virus was carried by monkeys that had been imported from the Phillipines.
    • 4 humans were infected and developed antibodies, but none of them became sick

Map of Ebola Reston Infected Monkeys in Philippines

slide15
Transmission
    • It is believed that the first human becomes infected with Ebola through contact with an infected animal.
      • An outbreak of Ebola-Zaire occurred in Gabon in 1996 after people had eaten an infected monkey.
      • One Scientist who had conducted an autopsy on a wild chimpanzee in the Tai Forest in Ivory Coast was diagnosed with Ebola-Ivory Coast in 1994.
slide16
People can become infected with Ebola if they come into contact with the blood or secretions of an infected person.
  • People can also become infected through contact with objects, such as needles, that are contaminated with secretions or blood.
    • In 1976, in England, a person became infected with Ebola-Sudan after being accidentally pricked with a contaminated needle.
slide17
Because the disease is easily transmitted, Nurses must wear protective clothing when interacting with a patient and must dispose of all needles and other medical supplies properly.

Nurses in full protective gear in Gabon, 2002

slide18
Patients who have died of the disease must be buried properly. Care must be taken that there is no contact with the deceased patient.

Burying Ebola Victim in Gabon, 2002

slide19
The Ebola Virus takes a psychological toll as well, causing devastated villagers to search for scapegoats.

Posted, February 21, 2003 8:37 AM EST

Brazzaville, Congo- Congolese villagers have stoned and beaten to death four teachers accused of casting an evil spell to cause an outbreak of the deadly Ebola disease that killed nearly 70 people, a local official said Friday. (Reuters)

slide20
Relief , joy and celebration after the Gabonese Health Ministry declares that the Ebola outbreak has ended. (May 6, 2002)
pleomorphic
Pleomorphic
  • Definition: having the ability to assume different forms or shapes
  • Four main shapes: long filamentous, U shaped, 6 shaped, circular
structure
Structure
  • Filoviruses are non-segmented negative strand
  • viruses
  • Composed of a helical ribonucleoprotein complex
  • (nucleocapsid)
  • Covered with a host-cell derived membrane envelope
  • Matrix between the envelope and nucleocapsid is
  • filled with a protein lattice
viral genome24
Viral Genome
  • Consists of seven genes
  • These genes encode seven proteins in the Marburg virus and eight in the Ebola virus
  • Both viruses have a 3’ leader and 5’ trailer sequence that is highly conserved and has a high degree of complementarity
  • These extragenic seguences are important in the initiation of transcription and replication
viral proteins
Viral Proteins

* Ebola virus only

  • NP: Nucleoprotein – the primary structural protein associated with the filovirus nucleocapsid
viral proteins26
Viral Proteins

* Ebola virus only

  • VP35: acts as a cofactor in transcription and replication of the viral proteins
viral proteins27
Viral Proteins

* Ebola virus only

  • VP40: a matrix protein, also the most abundant viral protein; may facilitate in the budding process
viral proteins28
Viral Proteins

* Ebola virus only

  • GP: Glycoprotein – makes up the virion spikes or peplomers and mediates entry into host cells through receptor binding
viral proteins29
Viral Proteins

* Ebola virus only

  • sGP: secreted from the cell, present in large amounts in the blood of Ebola victims; may help to inhibit the immune response
viral proteins30
Viral Proteins

* Ebola virus only

  • VP30 – a minor nucleoprotein that may be involved in securing the RNA to the C terminus of NP
viral proteins31
Viral Proteins

* Ebola virus only

  • VP24: unknown function, possibly a matrix protein
viral proteins32
Viral Proteins

* Ebola virus only

  • L: Polymerase L – acts as the polymerase and is the largest and least abundant viral protein
entrance into cells
Entrance into Cells
  • Mediated by the Glycoprotein on the envelope surface
structure of gp
Structure of GP
  • Precursor form GP0 is cleaved yeilding GP1 and GP2, they are connected via one disulfide bond
  • Form a heterodimer
  • Peplomers are then formed by the association of three of these heterodimers to form a homotrimer
  • GP2 is responsible for trimerization, fusion of the envelope and cell, and has an immunosuppressive motif
  • GP1is the receptor binding domain
receptor lipid rafts
Receptor - Lipid Rafts
  • Receptor, while for most cells unknown, appears to be located in LIPID RAFTS : less fluid areas of the membrane high in cholesterol and glycosphingolipid; the cholesterol-binding caveolin is also closely associated with the rafts
endocytosis
Endocytosis
  • Caveolae are present in the plasma membranes of most cell types and are thought to form from lipid rafts
  • The major structural protein is caveolin, a multipass protein
  • Caveolae invaginate and collect their cargo proteins, but do not require the assembly of a cytosolic protein coat
transcription
Transcription
  • Takes place in cytoplasm of cell
  • The seven genes are transcribed to produce seven monocistronic polyadenylated mRNA’s
  • Each gene has a conserved transcriptional stop and start sequences
  • Transcripts are thought to have 5’ caps
  • Gene overlaps - function unknown
unusual gp transcription
Unusual GP Transcription
  • In the Ebola Virus the GP gene codes for GP and sGP
  • sGP is the primary gene product
  • Full length GP is expressed by transcriptional editing of a single adenosine at a run of seven uridine residues in the genomic RNA
translation
Translation
  • sGP and GP are translated by membrane bound ribosomes and enter the ER and follow the exocytotic transport route to the cell surface
  • All other viral proteins are translated by free ribosomes in the cytosol
replication
Replication
  • Build up of proteins signals switch to replication
  • Switch results in synthesis of + sense RNA as a template
  • Depletion of proteins causes switch back to transcription, eventually equilibrium
immune system evasion
Immune System Evasion
  • Host dies with little evidence of an immune response
  • Mitosis of lymphoid cells seen to decrease 2-3 days postinfection with eventual apoptosis
  • Swelling of MPS and stromal cells and eventual lysis
  • Dendritic (antigen-presenting) cells also undergo apoptosis
immune system evasion48
Immune System Evasion
  • sGP may bind to neutrophils and inhibit their activation
  • sGP as a decoy? – absorb neutralizing antibodies
  • VP35 may act as an IFN antagonist
  • GP2 may have an immunosuppressive role
  • Ebola shown to inhibit induction of immunomodulatory and antiviral genes in endothelial cells (MHC I, IFN, etc…)
cytotoxicity hemorrhage and shock
Cytotoxicity,Hemorrhage, and Shock
  • GP expression causes downregulation of the cell-surface expression of integrins – cell rounding and detachment seen
  • Disruption of cell functions in general
  • Release of vasoactive agents (cytokines, chemokines, histamines and peroxidases) from infected monocytes and endothelial cells could increase hemorrhaging and induce shock
risk factors
Risk Factors
  • Travel to Asia or Africa
  • Handling of animal carcasses
  • Contact with sick animals or people
  • Arthropod bites within 21 days of onset of symptoms
  • Transmission is highest during latter stages of illness.
reservoir unknown
Reservoir Unknown
  • Bats?
  • Birds?
  • Insects?
  • Plants?
spread of ebola
Spread of Ebola
  • Direct contact with the blood and/or secretions of an infected person. (Family setting)
  • Contact with objects, such as needles that have been contaminated with infected secretions. (Health care setting)
ebola invasion
Ebola Invasion
  • Effects innate immune system (non-specific responses)
  • Enters through broken skin, mucous membrane or exchange of bodily fluids
  • Can also enter through ingestion, inhalation, injection of infectious material
ebola basics
Ebola Basics
  • Incubation period of 2-21 days
  • Mortality rate of 50-90%
  • Some primary targets are hepatocytes and endothelial cells, which produce the greatest amounts of furin in the human body
  • Stable at room temperature but is destroyed at 60 0 C.
  • Also destroyed by gamma and UV radiation, lipid solvents, and bleach
marburg basics
Marburg Basics
  • Incubation period of 2-14 days
  • Mortality rate of 23-25%
  • Stable at room temperature but is destroyed at 60 0 C.
  • Also destroyed by gamma and UV radiation, lipid solvents, and bleach
unsuspecting victim
Unsuspecting Victim

Your eyes are red and itchy. You're feeling a little stuffed up. Your body aches, and you feel warm.

You think you have a case of the flu coming on. Nothing a few good nights' rest won't cure, you think. The next morning, your head throbs. Your skin aches. You feel feverish, and your chest hurts. You can't get out of bed.

In the new few days, your fever skyrockets. You are disoriented and delirious. You throw up and notice the vomit is laced with blood. Next, you feel a liquid trickle out of your ears. With horror, you realize that it's more blood. Soon blood is seeping from your nose, gums, and eyes. The pain is excruciating. Inside your body, an army of microorganisms eats away at your veins and arteries and turns your organs into a sort of bloody cottage cheese. In 36 hours, you're gone. You die in a pool of blood that has oozed out of every part of your body.

early symptoms
Early Symptoms

The first signs usually are:

  • Prolonged fever that does not respond to antimalarial treatment or antibiotics
  • Joint pains and generalized body aches
  • Headache
  • Generalized weakness
  • Nausea and vomiting
  • Abdominal pain and diarrhea
  • Fatigue
  • Arthritis
  • Sore throat
  • Rash
  • Hiccups
after 5 7 days
After 5-7 Days

The fever may get associated with spontaneous bleeding e.g.:

  • Bleeding from the gums, nose, eyes, ears
  • Eyes may turn red (conjunctivitis)
  • Anal bleeding or bloody diarrhea, gastrointestinal bleeding
  • Genital swelling (labia and scrotum)
  • Bleeding from the skin
  • Difficulty in swallowing and dryness of the throat
  • Increased sense of pain in skin
  • Blood does not clot
  • Depression
  • Hypotensive shock
  • Liver damage
treatment for ebola and marburg
Treatment for Ebola and Marburg
  • Isolation and quarantine
  • Quick containment
  • No standard treatment
  • Supportive therapy, which includes balancing the patient’s fluids and electrolytes, maintaining their oxygen status and blood pressure, and treating them for complicating infections.
  • Mechanical ventilation, renal dialysis, and antiseizure therapy may be required.
what is the key to survival
What is the key to survival?
  • Demise or improvement usually occurs around day 7 to 11, when humoral antibody response can be detected.
  • Known that patients who die usually have NOT developed a significant immune response to the virus at the time of death.
convalescence and recovery
Convalescence and Recovery
  • Slow – takes 5 weeks or more
  • Can still harbor infectious viral particles up to 82 days after presentation
  • Weight loss and amnesia in early stages of recovery
survivors
Survivors
  • Psychosocial disturbances
  • Loss of memory
  • Central nervous system disorders
  • Loss of hair, hair elasticity and hair drying
  • Permanent hearing loss
  • Arthralgia
  • Uveitis
  • Orchitis
death and burial
Death and Burial
  • Villagers traditionally help sick, transport and kiss the dead
  • Wash and dress body for the afterlife
  • Burial practices last days
  • Dead buried near home
  • Hiding of bodies
clinical diagnosis of ebola
Clinical Diagnosis of Ebola
  • In early stages, it is difficult to diagnose because early symptoms, such as red eyes and a skin rash, are nonspecific and are similar to other diseases that occur much more frequently.
  • Use RT-PCR and ELISA to diagnose Ebola and Marburg.
enzyme linked immunosorbent assays elisa
Enzyme-linked immunosorbent assays (ELISA)

Detects early immunoglobuling (Ig) M antibody responses to the VHF-causing agents

challenges to vaccine development
Challenges to Vaccine Development
  • In past, rare occurrences of Ebola and remote locations of outbreak did not favor vaccine development.
  • Also required industrial support, which was not feasible since it was predicted there would be no market for the vaccine.
  • However, this changed with the existing threat of bioterrorism. Now Ebola is categorized as a ‘List A agent’.
ebola protection using immunotherapy
Ebola Protection Using Immunotherapy
  • Antibody titers against Ebola virus GPs are detected in patients who recover. However, serum from recovered patients did not consistently protect against infection or exhibit neutralization of virus replication in cell culture.
  • Passive transfer of antibodies in animal models only delays onset of symptoms and does not alter overall survival.
ebola protection using immunotherapy69
Ebola Protection Using Immunotherapy
  • Monoclonal antibodies isolated from bone marrow of recovered patients confer immune protection in a murine model of Ebola virus infection and in guinea pigs.
  • But it is relatively easy to protect against infection in the mouse model and protection of guinea pigs required a high dose of antibody administered very close to the time of virus challenge.
  • Conclusion: antibodies alone do not provide protective immunity in a natural context. May not be applicable to humans.
antiviral therapy
Antiviral Therapy
  • Use of S-adenosyl-L-homocysteine hydrolase inhibitors.
  • The drugs are active in vitro and in mouse and nonhuman primate models.
  • Drugs act through accumulation of S-adenosylhomocysteine and its selective inhibition of virus methylation reactions.
blood transfusions
Blood Transfusions
  • In 1995 Zaire outbreak, 8 patients given blood transfusions from individuals who recovered from Ebola.
  • 7 out of 8 patients survived.
  • However, study size was small and patients were young so actual effectiveness remains unknown.
vaccine development
Vaccine Development
  • Vaccine made with heat inactivated virions but level of protection was inconsistent. Guinea pigs were partially protected in one study and 4 out of 5 baboons survived challenge.
  • However, inactivated virions did not induce sufficient immunity in hamadryl baboons against a lethal challenge.
  • May not be effective in humans.
vaccine with evlp
Vaccine with eVLP
  • Recently, vaccine developed that is based on a single or combinations of virus-encoded structural proteins to induce immunity.
  • After vaccination with eVLP (Ebola virus-like particles), mice developed high titers of Ebola virus-specific antibodies, including neutralizing antibodies. The mice were 100% protected from Ebola virus.
protective materials
Protective Materials
  • Rubber boots which can be disinfected
  • Washable trousers over the boots
  • Washable jacket or blouses with long sleeves which can hold at the wrists
  • Rubber aprons which can be disinfected or disposed
  • Two pairs of latex gloves for certain manipulations or rubber gloves (heavy duty gloves)
  • Masks
  • Protective eye wear (glasses/goggles)
  • Headgear
weaponization
Weaponization
  • Characterized as “class A” weapons

because of their:

      • High virulence
      • Demonstrated aerosol infectivity in the laboratory
      • Ability to cause a state of intense fear and anxiety
slide77
Most likely method of attack would be aerosolization of virus into highly infectious particles in the 1-5 micrometer range. (particles remain suspended in air)
      • Although protective measures are in place to prevent contamination of food and water supplies, it would be impossible to ensure a constant supply of purified air.
      • The tremendous surface area of the lungs make them highly susceptible to microbial/viral infection.
slide78
A large scale attack would seem unlikely, as such an attack would require correct conditions of wind, temperature and humidity.
  • Terrorists are much more likely to carry out a smaller attack via a vulnerable ventilation system.
slide79
Difficulty in Detection
      • If terrorists were to carry out an attack, it would be a week before the first cases of illness appeared. (not known if disease is contagious in incubation phase)
slide80
Even after the illness appeared, it would be very difficult to determine that the illness was caused by a filovirus because of:
    • The similarity of the early symptoms of Ebola and Marburg, to those of other diseases
    • The unlikelihood that a case of these diseases would occur outside of Central Africa.
slide81
It is during this period (the opening phase of the outbreak) that the possibility of transmission of the disease is greatest.
    • Family members and health care workers who are treating the diseased person, but do not yet know the nature of their illnesses have an extremely high risk of contracting the virus.
  • The Detection of a deliberately caused outbreak will be based on the detection of an usual number of severe illnesses within a short period of time.
slide82
Availability of filoviruses
      • Samples of Marburg and Ebola were distributed to many research laboratories after their initial outbreaks in the 1960’s and 1970’s. It is feared that samples may have been stolen and distributed to wealthy terrorist organizations.
      • Aum Shrinkyo (Japanese cult responsible for Sarin gas attack on Japanese subway) has reportedly attempted to obtain the Ebola virus by sending some of its members down to Zaire in the early 1990’s.
slide83
Independent terrorist organizations may have a sympathizer infiltrate a BSL-4 lab with the intent of stealing a filovirus sample or they may attempt to purchase it from a scientist working in the lab.
    • Attempts are being made to improve security at these labs, but detecting the loss of the tiny volume of seed material needed to start a new culture is extremely difficult.
slide84
The Soviet Union reportedly took an active interest in filoviruses and their potential for use in bio-weapons.
      • Soviet laboratories acquired a sample of the Marburg Virus after the 1967 outbreak.
      • Research reports published by Russian investigators after the collapse of the Soviet Union show a strong interest in the stability of freeze dried Marburg virus, and its aerosol infectivity.
slide85
Soviet Scientist Nikolai Ustinov accidentally pricked himself in the finger with a syringe that contained Marburg Virus.
  • Ustinov began to vomit blood, pass bloody black diarrhea, and sweat blood from his pores.
  • Scientists kept this strain of Marburg, named Strain U , after Ustinov and processed it into inhalable dust.
slide86
The strain was extremely potent.
    • Upon testing, it was found that only one to five particles of Variant U, lodged into the lungs of a monkey, was almost guaranteed to make the monkey crash and die ( It takes 8000 spores of Anthrax in the lungs to guarantee death)
slide87

Conclusion

  • In addition to the sickness and death that it would cause, a filovirus attack would cause tremendous disruption of social and economic activity.
  • Ebola has the benefit (to terrorists) of having a reputation for causing horrifying illnesses.
  • Increased anxiety would occur if people were to see the effects of the disease, as well as the full protective gear that law enforcements officials, doctors, and nurses would be wearing.