Hemorrhagic Viruses Flashcards
Describe the structure of Flaviviridae?
small, enveloped, nonsegmented,
(+) strand RNA virus
What are the three genera of Flaviviridae?
- Flaviviruses
- Pestiviruses
- Hep C virus
What are some important subtypes of Flaviviruses?
- Dengue virus
- Yellow fever virus
How do Flaviviridaes enter cells?
pH-dependent endocytosis
Describe the replication process of Flaviviridae (and all + strand RNA viruses).
The genomic RNA has a 5’-cap (like host mRNAs) and is translated by host ribosomes to generate a single polyprotein, which is then cleaved by a combination of viral (cis-cleavage) and host (trans-cleavage)
proteases.
Cleavage of polyprotein generates the viral RNA-
dependent RNA polymerase which replicates the genomic RNA.
Structural proteins (capsid and envelope glycoproteins), which are also derived from the polyprotein, assemble genomic RNA into virions which “bud” into the endoplasmic reticulum or Golgi and enveloped viruses released from cells following transport to the cell surface.
T or F. All Flaviviridae are transported via insect vectors.
T. They are the most important group of arboviruses (arthropod-borne viruses) in terms of disease causation.
What is the disease course of Flaviviridaes?
- initial replication at site of infection (endothelium or epithelial cells)
- next, replicates in macrophages, spleen or lymph nodes- aka primary viremia (3-7 days post exposure)
How does most Flaviviridae disease progress after primary viremia?
most don’t progress, so the result is a mild systemic disease
However, some Flaviviridae infections can progress. What happens?
If infection is not controlled by immune response, then secondary viremia ensues.
Secondary viremia results in severe systemic disease (e.g. hemorrhagic fever/shock syndrome).
Where is Dengue fever common?
Primarily in South America, Southeast Asia, and Africa.
Most cases of dengue in the U.S. have been acquired abroad.
How does classical dengue fever present?
self-limited
- high fever (sustained up to 6-7 days)
- headache
- retrolobullar pain
- lumbosacral aching
- conjunctival congestion
- facial flushing
about 2-7 day after initiation
The initial symptoms are followed by generalized myalgia with increasing severity of muscle and joint pain. (Dengue fever is sometimes called “bonebreak fever” due to the severity of the bone pain)
Are there any symptoms present with CDF in the first two days?
A mottled rash may appear on the first or second day and often patients complain of a metallic taste in their mouths.
Lab findings of CDF?
-thrombocytopenia (less than 100K/ul)
What is DHF characterized by?
diffuse capillary leakage of plasma and a hemorrhagic diathesis.
What symptoms signal the development of DHF?
- Abdominal pain in conjunction with restlessness
- change in mental status
- hypothermia
- drop in the platelet count
If left untreated, dengue hemorrhagic fever most likely progresses to what?
dengue shock syndrome.
Increased vascular permeability results in:
hemoconcentration, decreased effective blood volume, tissue hypoxia, lactic acidosis, and shock.
What are some common signs that dengue shock syndrome is developing?
- abdominal pain,
- vomiting, and
- restlessness.
Patients also may have symptoms related to circulatory failure
In >90% of the cases of fatal DHF, there is evidence for that the person had been infected previously with at least one heterologous dengue serotype. What does this indicate?
Indicates that an immune-mediated pathology initiates the events that cause the hemorrhagic syndrome
Diagnosis of DHF?
- fever
- hemorrhagic manifestations (hemoconcentration, thrombocytopenia, positive tourniquet test)
- circulatory failure (hypoproteinemia, effusions)
- hepatomegaly
For, crab, harry, and hermione
Because the signs and symptoms of dengue fever are nonspecific, and symptoms can be easily confused with those of other diseases such as malaria, leptospirosis and typhoid fever, laboratory confirmation of dengue infection is important. Like what?
1) Serodiagnosis is made on the basis of a >4-fold rise in antibody titer in paired IgG or IgM specimens.
o Other diagnostic methods include:
Culture of virus from serum (or autopsy tissue)
Detection of viral genome sequences by RT-PCR
Where is yellow fever common?
South and Central America, and in Africa.
What are the three transmission cycles of yellow fever virus?
jungle (sylvatic),
intermediate (savannah), and urban
Describe the jungle cycle.
The jungle (sylvatic) cycle involves transmission of the virus between primates and mosquito species found in the forest canopy. The virus is transmitted by mosquitoes from monkeys to humans
Describe the intermediate cycle.
Involves transmission of virus from mosquitoes to humans living or working in jungle border areas. In this cycle, the virus can be transmitted from monkey to human or from human to human via mosquitoes.
Describe the urban cycle.
The urban cycle involves transmission of the virus between humans and urban mosquitoes, primarily Aedes aegypti. The virus is usually brought to the urban setting by a viremic human who was infected in the jungle or savannah
Symptoms of yellow fever?
“flu-like” malaise that progresses to a severe hemorrhagic fever.
- Hemorrhage of the stomach lining often results in patients having “Black Vomit”.
- Progressive liver involvement results in marked jaundice with increasing levels of serum transaminases owing to direct viral-mediated liver damage.
How YF diagnosed?
- any one of the following:
1) Virus isolation (i.e. incubating blood sample with cell lines to observe CPE)
2) Serologic identification using ELISA to detect IgG or IgM
3) Detection of viral genomic sequences by RT-PCR
T or F. There is a vaccine for YF
T. Live, attenuated
Bunyraviridae viruses are transmitted via insects and rodents. Describe their structure.
-enveloped, sphericla particles with a segmented, single-strand, (-) sense RNA genome
What are some of the subtypes of Bunyraviridae?
- Rift Valley fever virus
- Crimean-Congo virus
- Hemorrhagic fever with renal syndrome (HFRS) virus (Hantavirus)
Describe the replication cycle of Bunyraviridae (and all - sense RNA viruses).
- Virus binds and is endocytosed.
- Low pH in endosome triggers conformational changes in the envelope glycoproteins protruding from the viral membrane and these changes induce fusion of the viral membrane with the membrane of the endosome, which results in release of the viral nucleocapsids into the cell cytoplasm. This is sometimes called virus uncoating.
- Viral RNA-dependent RNA polymerase (RdRP), which is associated with the nucleocapsids, transcribes (+) sense mRNAs, which have 5’-caps and 3’ poly A, thus resembling host mRNAs
- Host ribosomes translate viral proteins from these virus-specific mRNAs.
- Viral RdRP also replicates the viral (-) sense genome by first making a (+) sense cRNA intermediate, then that is used as a template to make new (-) sense genomes (or vRNAs).
- (-) sense genomes are assembled and virus particles are released by budding.
T or F. RVFV is not found in the US.
T. but it is a potential bioterrorism agent
How is RVFV spread?
mosquitos mostly (transmitted to livestock mostly and can cause abortion)
There are vaccines available, and immunization of livestock is the most effective way to control and prevent the disease
Symptoms of RVFV infection?
Acute, self-limiting febrile illness characterized by flu-like symptoms
Does RVFV progress often?
No, Rarely (2%), symptoms progress to a severe form of disease which culminates in a hemorrhagic hepatitis
What are the symptoms of a progressive RVFV infection?
As symptoms progress, often mistaken for early stage meningitis (e.g. stiff neck, photophobia, vomiting)
Symptoms often include:
– Fever
– Encephalitis
– Retinal vasculitis (which may lead to blindness)
There is no established course of treatment for patients infected with RVFV.
What is Crimean-Congo transmitted by? Where is it common?
- ticks
- common in Middle East, Africa, and Europe
Symptoms of CCHFV?
headache
limb pain
bleeding from many orifices
Clinical disease is rare, but is severe in infected humans, with a 30% mortality rate.
What organs does CCHFV target?
the liver and vascular endothelium
What causes hemorrhagic fever with renal syndrome?
found primarily in Europe and Asia.
Human infection results from exposure to aerosolized urine, droppings, or saliva of infected rodents or after exposure to dust from their nests
Symptoms of HFRS?
Symptoms usually develop within 1 to 2 weeks after exposure
– Liver and vascular endothelium are targeted
– Symptoms include: • Fever • Hemorrhage • Acute renal failure – Over 15% mortality rate
Describe the structure of Arenaviridae viruses.
-enveloped, segmented, ambisense RNA virus
How are Arenaviridae viruses transmitted?
inhalation of aerosolized virus from rodent excreta (similar to the Bunya/hantaviruses causing HFRS)
What are the subtypes of Arenaviridae viruses?
Lassa fever virus (Africa)- Old World
South American Hemorrhagic Fever Viruses- New World
How do Arenaviridae viruses replicate?
pH-dependent pathway following endocytosis.
• Following uncoating transcription and replication occurs by a nonconventional “ambi-sense” strategy.
o The genome is first used as a template for transcription and the NP and L mRNAs are produced from either the L (long) or S (short) RNA segment.
o The polymerase then produces a full-length antigenome for each of the segments.
o The “(+)”-sense antigenome is then used as a template for transcription of the glycoprotein mRNA.
o Virus particles are then assembled and released from the cell surface by budding.
Describe Adenovirus infections
Most infections are mild or subclinical
Severe multisystem disease is believed to occur in 5-10% of total infections.
o Illness begins insidiously with fever, weakness, malaise, joint and/or lumbar pain, cough, and severe headache.
o In severe cases, illness progresses to include prostration, dehydration, abdominal pain, and facial or neck edema.
o Lymphopenia, thrombocytopenia, and defects in qualitative platelet function are found during this stage
T or F. Vaccines exist for Adenoviruses.
F. However, intravenous ribavirin has been shown to reduce the severity of illness caused by arenaviruses producing hemorrhagic fever.
Filoviridae are viruses that cause Severe hemorrhagic Shock syndromes. Describe their structure.
- enveloped
- pleomorphic rod-shaped virions
- nonsegmented
- (-) strand RNA
Filoviruses are highly transmissible viruses that cause a devastating hemorrhagic shock syndrome in both humans and non-human primates.
Two genera of Filoviridae:
- Marburgvirus
- Ebolavirus (species: Zaire, Sudan, Reston, Tai Forest & Bundibugyo)
How do Filoviridae replicate?
- Entry by endocytosis.
- Synthesis of viral mRNAs by the viral RNA-dependent RNA polymerse.
- Replication of antigenome and genomic RNAs
- Assembly and release by budding at the cell surface.
How does transmission of Filoviridae occur?
- during human outbreaks results from direct contact with infected patients.
- aerosol transmission may occur; however, aerosols have not been implicated in any of the human outbreaks to date.
- Bats (fruit bats) are a known reservoir, but do not exhibit disease.
- Bodily fluids including tears, sweat, vomit, semen and breast milk contain virus.
What cells are the initial target of filoviruses? What do this lead to?
-macrophages/monocytes leading to a cytokine storm
Where do filoviruses go once they disseminate in blood?
liver, kidney and spleen where high-level virus production ensues
What happens once filoviruses reach the liver, kidney, and spleen?
loss of platlets and other immune cells leads to the coagulation and vascular abnormalities
How do filovirus infections manifest clinically?
- Gross pathological changes in fatal cases include hemorrhagic diatheses into the skin, mucous membrane, visceral organs and the lumen of the stomach and intestines.
- Swelling of the spleen, lymph nodes, kidneys and the brain.
- Lesions on several organs including the liver. –> Lesions contain masses of filovirus nucleocapsids.
T or F. Ebolavirus is characterized by rapid onset of symptoms.
T.
Initially patients develop nonspecific flu-like symptoms such as fever, myalgia, headache, vomiting, diarrhea (cytokine mediated).
o May include development of a maculopapular rash.
o Unless virus replication is halted, there is rapid progression to hemorrhagic disease
What is the incubation period for Ebolavirus?
typically 4-10 days, but can be as long as 21 days.
What is the cause of death in Ebolavirus patients?
hypovolemic shock and systemic organ failure
What is the treatment for Ebolavirus?
Early supportive care with fluid and electrolyte replacement
What is the main goal in treatment of Ebolavirus?
To keep patient alive sufficiently long so they can mount an immune response to the virus.
Patients who survive generate a robust, protective immune response (neutralizing antibody response)
Convalescent sera from recovered patients has been used to treat patients who subsequently survived
There are no current (Spring 2016) vaccines for Ebola, however many are showing promise. Name some.
1) ZMapp – combination of 3 mouse-human chimeric monoclonal antibodies that neutralize virus infectivity.
2) Ebola vaccines – Two were used in West Africa. Consist of chimeric viruses expressing Ebola glycoprotein.
