Reddy: Viral CNS Infections I Flashcards
RNA Viruses: (7)
- Picornaviruses
- Flaviviruses
- Togaviruses
- Reoviruses
- Rhabdoviruses
- Bunyaviruses
- Retroviruses
Picornaviruses: (3)
Polio, Coxsackie, Hep A
Flaviviruses: (3)
West Nile Virus, Yellow Fever Virus, dengue
Togaviruses: (3)
Western Equine Encephalitis, Eastern Equine Encephalitis, Venezuelan Equine Encephalitis
Reoviruses: (1)
Colorado Tick Fever
Rhabdoviruses:
Rabies
Bunyaviruses:
California Encephalitis
Retroviruses:
HTLV-1, HIV
Herpesviruses: (3)
HSV-1, HSV-2, VZV
PICORNAVIRUSES
• Basics:
- Small RNA genome
- 5 genera based on physical properties and nucleotide sequence homology
Picornaviruses
Enterovirus:
Diseases of human (and other) alimentary tract (Polio, Coxsackie A and B, ECHO)
Picornaviruses
Rhinovirus:
Nasopharyngeal region (common cold)
Picornaviruses
Aphthovirus:
Foot and mouth disease of cloven footed animals
Picornaviruses
Hepatovirus:
Human hepatitis A virus
Enterovirus, Hepatovirus and Cardiovirus
Structure:
Growth:
o Structure: no envelope o Growth: • Resistant to low pH • Grows at 37 degrees C • Resistant to detergents (no envelope)
Enterovirus, Hepatovirus and Cardiovirus
Transmission:
Primary Infection:
o Transmission: fecal-oral
o Primary Infection: GI tract
Enterovirus, Hepatovirus and Cardiovirus
CNS Infections:
Progression to CNS infection depends on:
o CNS Infections: result in paralysis and encephalitis
• Progression to CNS infection depends on viral inoculums, viral infectivity and host immunity
Rhinovirus and Aphthovirus
Growth:
- Labile at low pH
* Grow at 33 degrees C
Rhinovirus and Aphthovirus
Transmission:
Primary Infection:
o Transmission: aerosols
o Primary Infection: upper respiratory tract
Picornaviruses
Capsid Structure
Enveloped?
What is Icosahedral nucleocapsid made of?
o Non-enveloped
o Icosahedral nucleocapsid (made of VP1, VP2, VP3 and VP4)
Picornaviruses
Capsid Structure
Protomer:
Full Capsid:
- Protomer: basic building block of the capsid; has one copy each of VP1, VP2, VP3 and VP4
- Full Capsid: consists of 60 of the above protomers
Picornaviruses
Genome Structure:
5’ End:
Genome Structure: +ssRNA
5’ End
• Capsid (structural protein) encoded by 5’ end
• Replication and translation controlled by long 5’ non-coding region (NCR)
➢ Has a clover-leaf secondary structure (Internal Ribosome Entry Site/IRES)
• Covalently linked to VPg protein
Picornaviruses
Genome Structure
3’ End:
o 3’ End:
• Protease (and other enzymes) encoded by 3’ end
• RNA synthesis controlled by a short 3’ NCR with poly A tail
Picornaviruses
Polyprotein:
- A single open reading frame codes for a single polypeptide divided into 3 regions (P1, P2, P3)
- Cleavage leads to 11-12 proteins
Picornaviruses
Regions:
P1,2,3
P1:
P1: encodes viral capsid proteins (VP1, VP2, VP3, VP4)
P2/P3
Encode proteins involved in protein processing:
Encode proteins involved in protein processing (2A, 3C, 3CD)
P2/P3
Encode proteins involved in genome replication:
Encode proteins involved in genome replication (2B, 2C, 3AB, 3B, 3CD, 3D)
Aphthoviruses and Cardioviruses encode:
Aphthoviruses and Cardioviruses: also encode a leader protein (L) before he P1 region
Picornaviruses
Ingestion:
Target Site:
- Ingestion: into GI tract (fecal-oral spread)
- Target Site: lymphoid tissue of the oropharynx and gut
Picornaviruses
Viral Replication:
- Viral Replication: occurs in oropharynx and/or small intestine
o Tonsils, cervical nodes, Peyer’s patches, mesenteric LNs
Picornaviruses
Initial Viremia
Transient vs Major:
Appearance of Ab leads to disappearance of virus and transient viremia
Without Ab, virus localizes in various organs leading to major viremia
Picornaviruses
Major Viremia:
Viral production mainly in:
In severe illness, ____ can result
- Major Viremia: can invade the CNS
o Viral production mainly in the grey matter (motor neurons of the anterior horns of the spinal cord and brain stem)
o In severe illness, paralysis can result
Picornaviruses
Excretion:
- Virus is excreted in the feces
.
Picornaviruses
Replication Cycle part 1
Attachment of virus to cellular R via _____ (can directly penetrate cell or be taken in via endocytosis)
_______ of the genome (____ released into cytoplasm
Viral translation to _______
_______ processing
o Attachment of virus to cellular R via VP1 (can directly penetrate cell or be taken in via endocytosis)
o Uncoating of the genome (RNA released into cytoplasm)
o Viral translation to polyprotein
o Protein processing (cleavage of polyprotein)
Picornaviruses
Replication Cycle part 2
Synthesis of RNA in membrane vesicles and copying of ___ to ___
Copying to multiple:
Additional proteins formed from:
_____ of RNA and viral protein assembly ‘
Release of new viral particles by _____
Synthesis of RNA in membrane vesicles and copying of +ssRNA to –ssRNA (used as template)
Copying to multiple +ssRNA from the –ssRNA templates
Additional proteins formed from new +ssRNA
Encapsidation of RNA and viral protein assembly
Release of new viral particles by cell lysis
Picornaviruses
Host Receptors
Some viruses use a single type of receptor: (3)
Some viruses use a single type of receptor (poliovirus, rhinovirus attach to Pvr)
Picornaviruses
Host Receptors
Some also require a co-receptor:
- Others also require a co-receptor (coxsackivirus A21 binds CD55 but also requires ICAM-1)
Picornaviruses
Host Protein Synthesis Shut Off
Basics:
• Host Protein Synthesis Shut Off:
- Basics: shut off host cell genes without affecting synthesis of their own proteins
Picornaviruses
Mechanism:
Enterovirus/Rhinovirus:
Aphthovirus:
- Mechanism: cleave cellular protein eIF-4G, resulting in protein synthesis shut off
o Enterovirus/Rhinovirus: do so using viral 2A protease
o Aphthovirus: does so using L protein
Picornaviruses
Viral Non-Structural Proteins
2A:
2B:
- 2A: viral protease (polyprotein cleavage)
- 2B: enhances vesicle formation in host (site of RNA synthesis)
Picornaviruses
Viral Non-Structural Proteins
2C:
3AB:
- 2C: RNA helicase (unwinds folded RNA during replication)
- 3AB: stimulates 3D polymerase activity and proteolytic activity of 3CD proteinase
Picornaviruses
Viral Non-Structural Proteins
3C:
3D:
VPg:
- 3C: viral protease
- 3D: RNA dependent RNA polymerase (RNA synthesis)
- VPg: provides poly U primer (primes RNA synthesis)
Picornaviral Diseases: (4)
- Poliovirus
- Coxsackie Viruses (A and B)
- Rhinoviruses
- Aphthoviruses
Poliovirus
Causes:
Progression:
Pathogenesis:
Causes: poliomyelitis (most severe disease caused by picornaviruses)
• 3 types of poliovirus, with most cases of disease being caused by type 1
Progression: only 1% of infected individuals progress to poliomyelitis
Pathogenesis: flaccid paralysis from destruction of motor neurons in anterior horn of spinal cord
Poliovirus
Last documented case:
IPV/Salk (inactivated):
Sabin/OPV (live, attenuated):
o Last documented case in the US: 1979 (due to vaccination)
• IPV/Salk (inactivated): less GI immunity and duration not known with certainty
• Sabin/OPV (live, attenuated): highly effective with life-long immunity (but risk of reversion)
Poliovirus
Eradication:
Eradication: possible due to vaccination (stable and long lasting immunity) and the fact that humans are the only reservoirs for poliovirus
Coxsackie Viruses (A and B)
Who is at risk?
Group A:
Children are the at risk population
o Group A:
• Aseptic meningitis (headache, stiff neck, fever)
• Herpangina (sudden onset fever with ulcers on tonsils and palate)
• Hand-foot-mouth disease (A16 specifically)
Coxsackie Viruses (A and B) Group B:
o Group B:
• Aseptic meningitis (headache, stiff neck, fever)
Rhinoviruses
Causes:
Treatment:
o Causes: common cold
o Treatment: pleconaril (also used against enteroviruses); no prospects for vaccines
Aphthoviruses
Causes:
Control:
o Causes: foot and mouth disease in animals
o Control: vaccination or slaughter of infected animals
• Note: vaccination is effective against symptoms but NOT against transmission to other animals
HIV
Neurological Complications:
Cell Tropism:
Neurological Complications: common among AIDS patients
o HIV found in CSF and brains of HIV patients (HIV Associated Dementia)
Cell Tropism:
o T cell tropic viruses
o Macrophage tropic viruses
o Neurotropic viruses (still unclear)
Potential Targets for HIV-1: (4)
o Entry
o Reverse Transcriptase (RT):
• NRTI: incorporate into growing strand of DNA and terminate DNA synthesis
➢ Zidovudine (AZT-thymidine analog), Didanosine, Zalcitabine, Stavudine, Lamivudine
• NNRTI: directly interact with RT enzyme to inhibit function
➢ Nevirapine, Delavirdine
o Integrase
o Protease: cleaves polyproteins into functional protein
• Protease Inhibitors: Ritonavir, Indinavir, Saquinovir, Nelfinavir
HAART:
- HAART: highly active anti-retroviral treatment
o Does not provide full protection against neurological damage in AIDs (because the BBB is only partially permeable to anti-retroviral agents)
Oncornaviridae: What is the only known human virus in this class?
HTLV
HTLV
Diseases:
o Adult T cell leukeumia (ATL)
o Tropical spastic paraparesis/HTLV-1 associated myelopathy (neurological disease)
HTLV
Transmission:
o Mother to child (breast-feeding)
o Sex
o Blood transfusion
o IV drug use
HTLV
Prevalent Areas:
Treatment:
- Prevalent Areas: Southwest Japan, Carribean basin, parts of South America, Central and West Africa
- Treatment: no specific and effective treatments o IFN-alpha + Zidovudine o Chemotherapy (limited success) o Zidovudine + Danazol + Vitamin C (temporary relief from TSP)
