Picornaviruses Flashcards
Picornaviruses- basic features
small, non enveloped, icosahedral viruses that contain single stranded, + sense RNA genome
- some serotypes commonly assd with certain diseases
- Neutralizing Ab against 1 serotype don’t neutralize viruses in other serotypes
***Most common respiratory virus causing infections in all ages
Medically important Picornaviruses
“PERCH” in FA
- Poliovirus
- Echovirus
- Rhinovirus
- Coxsachieviruses (CBV - serotypes 1-6; CAV: 1-24)
- Hepatitis A virus
Enterovirus genus includes different species: Polio, Echo, Coxsackie, Rhinovirus, and Enterovirus serotypes
- those within species group can combine genetic material
- lots of veterinary pathogens and a few that infect humans but medical significance not well defined (Parechovirus, Kobuvirus, Human cosaviruses–genus pending)
Enterovirus
- common infections in US but most subclinical without disease
- can infect/cause disease in every organ system
- Diagnose via isolate in cell culture, PCR useful for amplification of nucleic acid
Hepatitis A Virus (HAV)
- frequent cause of acute hepatitis in US
- Widespread use of vaccine has reduced cases but outbreaks from fecal-contaminated food or childcare centers common
- relatively benign form of viral hepatitis, usually subclinical or acute self-limited
Rhinoviruses
> 100 serotypes classified in 3 species
- Human Rhinovirus A, B, C
- so many serotypes + tendency for immunity to wane over time = most frequent cause of common cold
Poliovirus immunity and vaccination
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Polio/Entero/Rhinovirus RNA
Virion particle: 60 copies each of 4 viral capsid proteins (VP1-VP4) + 1 viral RNA
Attachment: specific cell receptor (CD155 for polioviruses, ICAM-1 or LDLR for Rhinoviruses, etc) reaches into canyon of virion particle. Virus-Receptor interactions primary determinant of host range/tissue tropism
Penetration/Uncoating: Pentamer extrusion model
Synthesis: Protein synthesis and RNA replication occur in cytoplasm.
Assembly: 60 copies of each protein creates virus particle (in the cytoplasm)
Pentamer extrusion model
Used by Polio/Entero/Rhinivoruses
- Genomic RNA extruded from virion into host cell cytoplasm through cell membrane. Suggests that viral RNA released into cytoplasm following endocytosis of virus bound to receptors
Replication of + strand RNA viruses
- occurs in cytoplasm
- Virion particles DO NOT contain replicase proteins
- Genomic RNA functions as mRNA upon release into cytoplasm –> viral replicase
- Viral replicase composed of RNA-dependent RNA polymerase and other enzymatic proteins (RNA helicase, capping enzymes, proteases) depending on type of virus
- RNA-dependent RNA polymerase copies viral (+) strand RNA into (-) strand RNA. (-) strand copied to make more (+) strand RNA molecules
- New RNA (+) strand molecules can be packaged into nucleocapsides to create virions, translated into viral replicaiton proteins, serve as template RNAs for more (-) strand RNA synthesis
-(+) RNA – (-) RNA – (+) RNA
Picornavirus Pathogenesis
- infections often innocuous since acquired immune response typically produces serotype specific neutralizing Ab before virus spreads to critical target organs
- Infection initiated at mucosal surface, go to draining lymph nodes and other peripheral tissues (depending on virus)
- Innate immunity (type I INF regulated antiviral responses) limit rounds of viral replication and tissue tropism
- 2ary viremia 5-15 days after the initial infection has potential to spread but acquired immune response has begun. IgM then IgG can neutralize virus particles to suppress viremia.Timing of acquired immune response corresponds to timing of symptomatic infection
Poliovirus epidemiology
- not unusual to have circulation of wild poliovirus in areas w/o paralytic case. For ever 100 ppl with cultured virus from stool 90-95 asymptomatic, 4-8 with minor illness (gastroenteritis, upper resp sxs or flu-like illness), 1-2 with aseptic meningitis and 0.1-1 with paralytic dz.
- Used to be endemic; Pre-industrial: would have most women of childbearing ages, so theirchildren would have IgG against 3 serotypes. Children often infected with each of the serotypes in first months of life but paralytic dz uncommon due to Ab.
- Industrial revolution – improved sanitation – children less likely to be infected early esp. in higher socioeconomic groups. Thus paralytic poliomyelitis became epidemic, first in more developed nations Older children struck with paralytic polio.
- Inactivated Poliovirus Vaccine (IPV) introduced by Salk– very effective but some lots weren’t completely inactivated and causes paralytic infections.
- 1960s, attenuated oral poliovirus vaccine introduced (OPV- Sabin)
Piliovirus pathogenesis
PRIMARY INFECTION
Day 0: ingest fecal material. Virus infects mucosal cells of pharynx/SI; associated lymph tissue also infected (tonsils, Peyer’s patches, draining LN). Fecal shedding 2-6 weeks
Day 1-2: Viremia: low level viremia
- infection fo non-neural tissues (sk muscle, brown adipose, etc)
Day 2–7: Seeded viruse replicates in skeletal muscle, brown fat cells, and other extraneural cells. This supports one or both pathways for CNS infection.
Day 7-14: CNS Infection
- only 0.5-2% Infections
- Get either Viremia across BBB or Axonal transmission up motor neurons
- Only motor neurons destroyed, sensory neurons spared. Cerebral cortex NOT infected.
Polio immunity/Vaccines
- Neutralizing Ab bind nucleocapsid, interfering with attachment/uncoating
- Natural, life-long immunity following infections (most often subclinical)
- Maternal Ab protect newborns for 6-8 weeks
- Humoral immunity does NOT prevent GI infection (no sterilizing immunity)
Vaccines:
Salk- inactivated Poliovirus vaccine (IPV)
Sabin - oral poliovirus vaccine (OPV)
Both are trivalent (against all 3 serotypes.
Both induce “herd immunity”
Inactivated Poliovirus Vaccine
IPV
- Killed virus that is injected
- Induces protective systemic IgM/IgG immunity
- no live virus precludes reversion of virus in vaccine
- Acceptable for immunocompromised
Disadvantages:
- Cost (more expensive than OPV)
- Injection
- Poor mucosal immunity
As of 2000, exclusive IPV recommended in US at 2, 4, 12 months of age
Oral poliovirus vaccine
OPV
- live attenuated
- oral admin easy
- inexpensive
- better mucosal immunity
Negatives:
- attenuated forms commonly revert to neurovirulent forms during replication in vaccinees
- Contraindicated in immunocompromised
- Revertant virus passed in stool and infects contacts (vaccine-associated paralytic poiomyelitis -VAPP)
about 1: 500,000 first time vaccinees or contacts acquire paralytic dz from OPV.
-Used almost exclusively in world until 1997. THen combo of IPV and OPV.
As of 2000, exclusive IPV recommended in US
Poliovirus eradication campaign
- WHO target to eradicate worldwide by Dec 31, 2000
- all time low of 150 cases in 2001
- > $300 million spent per year in US on vaccinations due to potential reintroduction of wildtype form elsewhere
- Current strategy involves continued vaccination worldwide, surveillance for paralytic polyomyelitis cacses, mass vaccination campaigns with OPV in regions where epidemic/endemic.
- Have National Immunization Days– even ceasefires in regional wars so vaccination occurs
- After 2+ years of surveillance in hwich no wildtype fpoliovirus found, strategy to completely cease OPV poliovirus vaccination simultaneously around the world. IPV will continue but cost considerations. New target date is 2019.
Potential pitfalls in eradication
- Individuals persistently secreting poliovirus (rare but documented)
- Transmission of OPV vaccine strains following cessation of vaccination
- Vaccine strains revert to wildtype
- Re-emergence of wildtype years after termination of vaccination programs from any source (frozen fecal samples, terrorists, undetected sources in population)—could be devastating
What 1 virus has been eradicated
Smallpox (variola) is only human pathogen ever eradicated but still have some in CDC and Russia
- some worry about use as weapon
- Eradication facilitated by virus only replicating in humans, near 100% attack rate (few subclinical infections so detection easy), and efficacious vaccine
Enterovirus, Rhinovirus, Hep A: Acid stable? Route? Primary infection site?
Enterovirus
- acid stable
- respiratory secretions/fecal-oral
- primary infection in pharynx/intestine
Rhinovirus
- NOT acid stable
- transmit via fomites, respiratory secretions
- Upper respiratory tract = primary infection site
Hep A
- Acid stable
- Fecal-Oral
- Primary infection in Pharynx/Intestine
What molecules of the virus & host define serotypes
- Neutralizing Ab from host
- Antigenic epitoes of capsid proteins in viral surface
epitopes on capsid proteins recognized by antibodies that neutralize infectivity
Name Human Enteroviruses
Enteroviruses = Genus of Picornavirus Family
- Inlcudes Poliovirus, Coxsackie, Enteroviruses, Rhinoviruses
Spectrum of dz and organ systems of Enteroviruses
**basically can infect/cause dz in every organ system, with some serotypes commonly associated with particular diseases
- Aseptic meningitis one of more common diseases from Enterovirus (2nd leading cause in 6-60 yo)
- acute onset fever, chills, headache, photophobia, pain on eye movement; N/V; headaches = “worst they have experienced”
- On exam: meningismus without localizing signs; CTs unremarkable
- typically recover w/o therapeutic intervention
- Neonatal infections
- Myocarditis/Endocarditis (mostly newborns/adol, YA)
- Hand-Foot and Mouth Dz
- Hemorrhagic Conjunctivitis
- Fever/Rash (most common cause of fever/rash in kids in summer/fall in US)
- Acute Flaccid myelitis (inflammed spinal cord)
Protective immune responses
- We make Ab to capsid protein epitopes to neutralize infectivity–have to make different antibodies for different serotypes
- Neutralizing IgG in blood will block viremia
- Neutralizing IgG block dz
- Neutralizing IgG will NOT block infection (not at mucosal surface)
- Neutralizing IgA Ab necessary at mucosal surface
Transmission/epidemiology. When are seasonal epidemics of enterovirus dz in US
- Enterovirus dz in US most common between June and November
- Fever/rash in kids
- URIs in children/adults
- Aseptic meningitis (often more severe in adults vs kids–peak late summer)
Pathogenesis (timing of immune response relative to spread of virus to target organs)
How timely you get an acquired immune response could prevent disease
often times response is fast enough that we don’t get bad disease?
Vaccine-Associated Paralytic Poliomyelitis
- associated with OPV vaccine– LAV virus reverts to wildtype and forms during replication in gut then sheds in feces.
- OPV recipients, contacts of recipients, immunocompromised recipients/contacts
