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Picornavirus Medical Glossary
Enteric disease: intestinal disease
Enterovirus- refers to oral-fecal transmission, not intestinal disease
Sequelae: condition following as a consequence of a disease
Frank cases of polio: CNS pathology
Encephalitis: inflammation of brain
Meningitis: inflammation of the meninges (membrane covering brain)
Aseptic Meningitis: meningitis in which no bacteria are cultured from CSF
Poliomyelitis: spinal cord inflammation from Polio virus
Bulbar poliomyelitis: brain stem inflammation from Polio virus
Pleurodynia: severe pain in lower chest (AKA: Bornholm disease, devil's grip)
Myocarditis: inflammation of heart muscle/myocardium
Pericarditis: inflammation of the sac around heart muscle/pericardium
Herpangina: A disease caused by types of coxsackievirus and marked by vesiculopapular lesions about 1 to 2 mm in diameter which
are present around the face and soon break down to form grayish yellow ulcers; accompanied by sudden onset of fever, loss of appetite,
dysphagia, pharyngitis, and sometimes abdominal pain, nausea, and vomiting
Dermatomyositis: inflammation of the connective tissue (muscle/skin)
Exanthema: rash
Bradykinin- 9 amino acid peptide, dilates blood vessels, increasing vascular permeability
Histamine- amine released by mast cells or basophils, dilates blood vessels and increases vascular permeability
On to the RNA viruses
Picornaviruses - ss positive sense RNA, non enveloped virus
- genome RNA is also the message RNA
- entero & rhinoviruses are most common viral infections
Enteroviruses - fecal-oral transmission
major viral cause of asceptic meningitis
Polio - poliomyelitis
- vaccine
Coxsackie viruses A- hand-foot-and-mouth disease
B- myocarditis, pericarditis
Echoviruses- asceptic meningitis
acute febrile illness
Rhinoviruses- common cold, > 100 serotypes, vaccine unlikely
Hepatitis A virus- covered in Hepatitis virus section
Noroviruses - norwalk-like disease: self-limiting GI disease
Coronaviruses- common cold, SARS, MERS
Arboviruses - Arthropod-borne viruses
Alphaviruses- Chikungunya
Flaviviruses- Yellow Fever, Dengue, West Nile, Nika
Replication
Cycle
(+) strand RNA viruses:
RNA genome can be
translated upon release
into cell
Replication mediated by
RNA-dependent RNA
polymerase
Picornaviruses: Shared Properties
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•
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small, naked icosahedral capsid
positive-stranded RNA genome (7,400-8,000 nt)
genomic RNA is infectious
replicate in cytoplasm; most viruses are cytolytic
Properties of Rhino- and Entero-viruses
pH sensitivity
Rhino viruses
Entero viruses
acid labile
acid resistant
Optimum Detergent Serotypes Transmission Site of primary infection
temp
sensitivity
33o C
>100
o
37 C Resistant
72
aerosol
oral-fecal
upper respiratory tract
gut
The capsids of entero-, cardio- and hepatoviruses are very resistant
to harsh conditions (pH, heat, moderate detergents) which allow
survival in sewage systems and gastrointestinal tract and facilitates
transmission by the fecal-oral route.
Enterovirus Epidemiology
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Asymptomatic shedding
puts the virus into the
environment
Virions are resistant to
harsh environment
Fecal-oral route of
transmission
Children are more
susceptible
World-wide distribution
Disease is more common
in summer
Enteroviruses
5-10 million annual infections in US
Human diseases caused by enteroviruses
Polio
Asymptomatic
yes
Meningitis
yes
Paralysis
yes
Febrile exanthems no
Acute respiratory no
Myocarditis
no
Orchitis
no
Coxsackie A
yes
yes
yes
yes
yes
yes
no
Coxsackie B
yes
yes
yes
yes
yes
yes
yes
Echo
yes
yes
yes
yes
yes
yes
yes
Entero (other)
yes
yes
no
yes
yes
no
no
Picornavirus Pathogenesis
1.
Entry via the oropharynx,
intestinal mucosa or upper
respiratory tract
2. Primary infection: lymphatic tissue
3. Spread to the target tissues: EV and
HAV spread by viremia
4. Disease factors: (I) target tissues,
(II) cytolytic capacity of the virus
5. Virus shedding: (I) feces, EV and
HAV, (II) nasal secretion (HRV)
Poliovirus
• An ancient disease
• Egyptian stele from the
second millennium B.C.
represents a young man
with an atrophic limb – a
sequelae of paralytic
poliomyelitis
• Before “vaccine era”,
21,000 paralytic cases per
year in the USA
Bulbar Poliomyelitis Involves Cranial Nerves
and Medullary Respiratory Center
1880s-Severe outbreaks in Europe and the U.S.
1938-National Foundation for Infantile
Paralysis is founded, later known as March
of Dimes
1954-Jonas Salk develops and tests killed
poliovirus vaccine on over 1.5 million school
children
1962-Albert Sabin develops live, attenuated
vaccine
Incidence of Polio in the USA
Famous Polio Survivors
* Alan Alda, actor
* Sir Arthur C. Clarke, scientist and science fiction author
* Francis Ford Coppola, film director
* Donovan, musician
* Ian Dury, rock musician
* Mia Farrow, actress
* Michael Flanders, British actor, broadcaster, and writer
* Arthur Guyton, physiologist
* Frida Kahlo, artist
* Alan Marshall, Australian author
* Joni Mitchell, musician
* Jack Nicklaus, golfer
* Kerry Packer, Australian media proprietor
* Yitzhak Perlman, violinist
* Franklin D. Roosevelt, US president, may have had polio
* Wilma Rudolph, athlete, later Olympic gold medalist
* Neil Young, musician
* John Thaw, British actor
Coxsackie A
Viruses
Hand-foot-and-mouth-disease
Asceptic Meningitis
Herpangina- tonsil vesicles, blisters
Coxsackie B
Viruses
Asceptic Meningitis
Pleurodynia- headache, fever, lower chest pain
Pericarditis, myocarditis
15 year mortality rate: ~15%
Viral & immune
mediated pathology
Echo- and Enteroviruses 68-71
Echo - Enteric cytopathic human orphan virus:
means no associated disease, MISNOMER
- acute febrile illness in children
- major cause of aseptic meningitis
(virally induced autoimmune syndrome)
Laboratory Diagnosis
 Serology: detection of specific IgM
 Virus isolation: from throat, stool, CSF
(coxsackieviruses and echoviruses)
 Virus propagation: primary monkey kidney cells;
suckling mice (especially for some CoxA)
 Virus identification:
 Use of specific antibody (neutralization, ELISA,
immunofluorescence)
 RT-PCR
Enteroviruses: Treatment,
Prevention, and Control
Antiviral drugs:
pleconaril replaces the natural lipid in the hydrophobic
pocket and blocks the entry of the viral genome;
effective only when administered early after infection
rupintrivir and other viral proteinase 3C inhibitors
Vaccines: available only for poliovirus
Control: improvement of hygiene and living conditions
Rhinoviruses
Rhinoviruses: Pathogenesis
•
The major cause of the common cold (~1/2 of cases)
•
Virions are liable to acidic pH –unable to replicate in
gastrointestinal tract
•
Virus grows best at 33oC (does not grow at 37oC) - replicate in
the upper respiratory tract, predilection for the nasal mucosa
•
Host cells: epithelial, fibroblast and B-lymphoblastoid cells
Rhinovirus Symptoms
- generally immune-mediated
•Infected cells release bradykinin and histamine,
which cause a “runny nose”
•Viral shedding through nasal secretion
Rhinoviruses: Epidemiology
•
Virions are resistant to drying and detergents
•
Transmitted by aerosols and person-to-person contacts
- wash your hands...
•
Infections are more frequent in the early autumn or the
late spring; highest in infants and children
•
most people average one infection every 1-2 years
Rhinoviruses: Treatment,
Prevention and Control
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Nasal vasoconstrictors: temporary relief; the use may
worsen the symptoms
•
Drugs: (i) arildone, rhodanine, etc. (similar to pleconaril)
block uncoating of the virus; (ii) enviroxime inhibits viral
RdRP; (iii) AG-7088 inhibits viral proteinase
•
Vaccines will not be beneficial because (I) more than 100
HRV serotypes, (ii) antibody response is transient (wane 18
month after infection)
•
Control: improvement of hygiene and living conditions
Noroviruses
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discovered in 1972
(+) strand RNA
non-enveloped capsids, stable
fecal/oral transmission
RT-PCR detection
Humans: Norwalk-like viruses (Noroviruses)
cause GI disease, usually self-limiting
- children: vomiting
- adults: diarrhea
• treat with oral hydration
• no cell culture or animal models: use human volunteers!
Norwalk-like Viruses
Virus strikes cruise ship
Nearly 250 sickened by Norwalk-like virus
Saturday, January 22, 2005 Posted: 1:33 AM
EST (0633 GMT)
(CNN) -- Nearly 250 people on a seven-day
Caribbean cruise were sickened by a Norwalklike stomach virus, which officials believe was
brought on board by a passenger previously
exposed to it, the cruise line said Friday.
Norwalk-like Viruses
Arboviruses
Togaviridae and Flaviviridae
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Positive single-stranded RNA genome
Enveloped viruses
Replicate in cytoplasm
Most of the viruses can replicate in
vertebrates and invertebrates and are
transmitted by arthropods – arboviruses
(arthropod-borne viruses)
Arboviruses:
Transmission
and
Maintenance
Flavivirus
Pathogenesis
YFV History
• 1648 - first report
• Prevalent in 1600s Atlantic trade routes
• Finlay (1881): hypothesis of mosquito transmission
Dr. Carlos Finlay
• Spanish American War-1898
• Reed (1900): proof of mosquito hypothesis,
Koch’s postulates for YFV
• Theiller: (1931 - YFV diagnostics), 1937- 17D vaccine
Dr. Walter Reed
Yellow Fever Endemic Zones
Travel requirements for vaccination with Yellow Fever 17D
S. America
Africa
Generally: Vaccination recommended
Vaccination required
Dengue Virus
• The biggest arbovirus problem in the world today (over 50
million cases per year.)
• Can cause dengue fever, hemorrhagic fever and/or hemorrhagic
shock (plasma leakage , increase in capillary permeability)
Areas infested with Aedes aegypti
Areas with Aedes aegypti and recent epidemic dengue
Dengue Hemorrhagic Fever (DHF)
1968–1980
5 Countries: 60
Cases
1981–2001
28 Countries
>93,000 Cases
2002- Rio de Janeiro: ~1 million infected with Dengue, ~2000 DHF, 134 dead
Dengue Virus
Antibody-dep. Enhancement:
Previous infection with with a different
Dengue seroptype increases likelihood
of developing DHF/DSS
The primary target cells of flaviviruses are
of monocyte-macrophage lineage.
Flavivirus infection is enhanced 2001000 fold by non-neutralizing antiviral
antibodies that promote virus binding to
Fc receptors.
Dengue Clinical Syndromes
• Undifferentiated fever
no or mild symptoms
• Classic dengue fever- “break-bone” fever
- fever, headache, muscle and joint
pain, rash, nausea/vomiting, pain behind eyes
• Dengue hemorrhagic fever (DHF)
• Dengue shock syndrome (DSS)
- DSS is DHF plus weak pulse, hypotension
Dengue - DHF-DSS
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Mortality of 5-30%
DHF - increased capillary permeability
Subcutaneous bleeding
Gum, nasal bleeding
Gastrointestinal bleeding
DSS - hypotension or narrow pulse pressure, rapid weak
pulse
• Hepatomegaly
Dengue prevention and therapy
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No specific antiviral therapy available.
Prevention of dengue in endemic areas - mosquito eradication
No vaccine available
A live attenuated vaccine candidate in Phase3 clinical trials,
fear of exacerbating DHF
• Treatment: supportive, fluids
Trouble Ahead?
• 2.5 billion people at risk world-wide
• In the Americas, 50-fold increase in
reported cases of DHF (1989-1993
compared to 1984-1988)*
• Widespread abundance of Aedes aegypti in
at-risk areas
West Nile Virus
• Zoonotic Flavivirus using avian amplifier
hosts, ornithophilic vectors.
• Strain highly infectious for North American
birds, causing mortality and high viremia.
• Overwinters in hibernating Cx. pipiens
mosquitoes.
• Vertical transmission efficiency?
• Overwintering in other species?
West Nile Virus Transmission
Cycle
West Nile Virus in the “Old World”
First isolated in Uganda, West Nile (1937)
• First known human outbreaks: Israel (1950’s)
• First isolation in Europe: Rhône Delta (1963)
• Largest epidemic: South Africa (1974)
• Now documented in at least 20 countries
• Recent human outbreaks: Algeria (1994); RomaniaBucharest (1996-97); Czech Republic (1997); DRC
(1998); Russia (1999), Israel (2000),
New World Outbreaks!!- North America (1999-present)
Proposed West Nile control procedures
Bush Sends Troops
To West Nile
West Nile Map
Bush outlines the details of Operation
Deep Desert Off! to reporters.
The Onion | September 18, 2002 | Issue 38•34
West
Nile
Spread
in
US
2000
2001
2002
West Nile Cases 2003
Stages of West Nile Virus Infection
Host Entry By
Mosquito Innoculation
First round of replication in the skin:
Langerhans dentritic cells (LDC)
LDC migrate to draining lymph nodes
Secondary round of replication occurs
Viremia
Viceral Organs
(Liver, kidney, spleen)
?
CNS
Destruction of neurons
Emerging Arbovirus infections:
Chikungunya & Zika Virus
Chikungunya:
Point mutation in viral envelope protein changed
mosquito tropism from A. aedis to A. albopictus
Emerging Arbovirus infections:
Chikungunya & Zika Virus
Zika:
Introduction into S. America, probably during 2014
World Cup
Arboviruses: Diagnosis,
Treatment and Control
• A variety of serologic methods and RT-PCR are used to identify the
virus. The presence of specific IgM is indicative of the acute or recent
infection. Some viruses elicit serologic cross-reactivity.
• No treatments exist other than supportive care
• The spread is prevented and controlled by eliminating insect vectors and
their breeding grounds
Arboviruses: Vaccines
• Yellow fever 17D strain is a safe and effective live viral vaccine.
Immunity is long and, possibly, protects from other cross-reacting
flaviviruses.
• Killed vaccines against EEE, WEE, Japanese and Russian springsummer encephalitis viruses are available.
• A vaccine against dengue virus is difficult to develop due to potential
risk for immune enhancement of the disease upon subsequent
challenge.