CNS VIRAL INFECTIONS (DR. REDDY)
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How many WBCs (per microliter of CSF) are indicative of an acute fungal or viral infection?
What % of PMNs in CSF is indicative of an acute fungal or viral infection?
How many RBCs (per microliter of CSF) are indicative of an acute fungal or viral infection?
How much glucose (per mg/dl of CSF) is indicative of an acute fungal or viral infection?
How much protein (per mg/dl of CSF) is indicative of an acute fungal or viral infection?
Match the following.
8. Herpes viruses
A. RNA virus
B. DNA virus
C. HSV-1, HSV-2 and VZV
D. Colorado tick fever
E. HTLV-1 and HIV
F. Polio, Coxsackie and Hepatitis A viruses
G. California encephalitis
H. WEE, EEE, and VEE
J. WNV, YFV and dengue
- 1. Picornaviruses - F. Polio, Coxsackie and Hepatitis A viruses
- 2. Flaviviruses - J. WNV, YFV and dengue
- 3. Togaviruses - H. WEE, EEE, and VEE
- 4. Reoviruses - D. Colorado tick fever
- 5. Rhabdoviruses - I. Rabies
- 6. Bunyaviruses - G. California encephalitis
- 7. Retroviruses - E. HTLV-1 and HIV
- 8. Herpes viruses - C. HSV-1, HSV-2 and VZV
What are the 5 genera of picornaviruses and what disease do they cause? (remember: R.E.A.C.H.!)
- Rhinovirus - common cold
- Enterovirus (polio, coxsackie A and B, echo virus) - diseases of the human alimentary tract
- Aphthovirus - foot and mouth disease in cloven-footed
- Cardiovirus - murine encephalomyocarditis
- Hepatovirus - human hepatitis virus A
What are the characteristics of an ideal vaccine? (remember: L.E.A.S.E.S.!)
- Easily Administered
What are some properties of the entero-, hepato-, and cardioviruses (picornaviruses)?
- resistant to low pH and grow at 37 degrees celsius
- no envelope - resistant to detergents
- fecal-oral route
- affects GI tract
- leads to CNS infections - paralysis and encephalitis
What are some properties of the rhino- and apthovirus (picornaviruses)?
- labile at low pH and grow at 33 degrees celsius
- acquired through aerosol inhalation
- affect URT
What is the organization/structure of picornaviruses?
- no envelope
- icosahedral capsid
- "clover-leaf" shape
- Internal Ribosome Entry Site (IRES) - regulates genome replication and translation
- 5' linked to VPg protein
- 3' controls RNA synthesis
Describe the polyprotein of picornaviruses and its derivatives.
- divided into 3 regions: P1, P2, P3 > yields 11-12 proteins
- P1 encodes viral capsid proteins (VP1, VP2, VP3, VP4) - encapsidates RNA during viral assembly
- P2 and P3 - encodes proteins involved in protein processing and genome replication
Which 2 picornaviruses encode a leader (L) protein before the P1 region of the polyprotein?
What are some characteristics of picornavirus host cell receptors?
- share cellular receptors (some use a single type receptor, i.e. polio and rhinoviruses)
- few viruses require a co-receptor (i.e. coxsackievirus)
Describe the replication cycle of picornaviruses.
- replicates in cytoplasm
- virus binds to cell surface receptor (via VP1)
- uncoating of genome
- viral RNA translation
- protein processing
- synthesis of RNA and copying of + stranded RNA to - stranded RNAs
- copying to multiple +RNAs from -RNAs
- additonal proteins from newly synthesized +RNAs
- encapsidation of RNA and viral assembly
- release of new viral particles by cell lysis
How do picornaviruses "shut off" host protein synthesis?
cleavage of host cell protein elF-4G (eukaryotic inition factor 4G) - mediated by viral 2A protease
Match the following.
1. viral protease
2. enhances the vesicle formation in host cells which serve as sites of RNA synthesis
3. RNA helicase
4. stimulates the 3D pol activity and proteolytic activity of 3CDpro
5. viral protease
6. RNA dependent RNA polymerase - RNA synthesis
7. provides poly(U) primer
- 1. viral protease - D. 2A
- 2. enhances the vesicle formation in host cells which serve as sites of RNA synthesis - B. 2B
- 3. RNA helicase - G. 2C
- 4. stimulates the 3D pol activity and proteolytic activity of 3CDpro - A. 3AB
- 5. RNA dependent RNA polymerase, RNA synthesis - F. 3D
- 6. provides poly(U) primer - C. VPg
What is the pathogenesis of picornaviruses?
- GI ingestion (fecal-oral)
- targets lymphoid tissue of oropharynx and gut > viral replication
- enters bloodstream
- virus can localize in various organs (viremia) > invasion of CNS
- primarily infection occurs in gray matter > paralysis
- virus is excreted in feces
What are the general characteristics of the poliovirus infection?
- causes most severe disease "poliomyelitis" - results from type 1 poliovirus
- destruction of motor neurons in the anterior horn of spinal cord > flaccid paralysis
- vaccines available: IPV (Salk) and OPV (Sabin)
True or false. Humans are the only reservoir for poliovirus.
What are the general characteristics of the coxsackievirus infection?
- children are at the most risk
- Group A and B cause aseptic meningitis - headache, stiff neck and fever)
- Group A causes Herpangina - sudden onset of fever with ulcers on tongue and palate
- Group A16 causes hand-foot-mouth disease (HFM)
- acute type 1 diabetes
What are the general characteristics of the rhinovirus infection?
- entry via URT
- causes common cold
- pleconaril against enteroviruses and rhinoviruses
- no vaccines are available
What are the general characteristics of the aphthoviruses infection?
- causes foot-mouth disease (FMD) - NOT THE SAME AS HAND-FOOT-MOUTH DISEASE!
- vaccine available - effective against symptoms but doesn't block transmission
What disease is usually associated with HIV and neurological disease?
What are the 2 subtypes of HIV?
- 1. T-cell trophic
- 2. macrophage tropic
What are the 4 target sites for HIV-1 antiviral agents? (remember: R.I.P.E.!)
- Reverse transcriptase
Describe the mechanism of action for reverse transcriptase inhibitors?
inhibits reverse transcriptase enzyme
Name 5 common reverse transcriptase inhibitors.
What are the 2 common non-nucleoside reverse transcriptase inhibitor analogues used to treat HIV?
What is the mechanism of action for non-nucleotide reverse transcriptase inhibitors analogues used to treat HIV?
directly interacts with reverse transcriptase and inhibits its function
What are the 4 common HIV protease inhibitors? (remember: R.I.N.S.!)
What is the mechanism of action for HIV protease inhibitors?
inhibit the function of the HIV protease
What are the 2 most common drugs that HIV patients build resistance to?
- reverse transcriptases
- protease inihibitors
What is the "cocktail" of HIV antiviral treatment?
1 nucleoside RTI + 1 (or 2) PI
True or false. HAART helps to provide full protection against neurological damage in AIDS patients.
False, because blood-brain-barrier is only partially permeable to antiviral agents.
Which virus was the first identified human retrovirus?
HTLV (human T-cell leukemia virus)
Which 2 diseases are caused by HTLV?
- Adult T-cell leukemia (ATL)
- TSP/HAM (tropical spastic paraparesis/HTLV-1 associated myelopathy - neurological disease
How can HTLV be transmitted?
- mother to infant - breastfeeding
- blood transfusion
- IV drug use
What areas is HTLV most prevalent?
- SW Japan
- S. America
- Central and West Africa
What are the current treatments for HTLV?
- no specific treatment is available
- IFN-alpha + zidovudine
- zidovudine + danazol + Vitamin C relieve TSP (Tropical spastic paraparesis)
What is the definition of an arbovirus?
A viruses that is spread to humans through an arthopod vector - flaviviridae and togaviridae families
What diseases do flaviviruses cause in humans and what are the common symptoms?
- Yellow fever
- West Nile virus
- Dengue fever
- Japanese encephalitis
- St. Louis encephalitis
- Tick-bourne encephalitis
- Symptoms: severe headaches, fever, chills, N/V/D
What are the 3 genera of flaviviridae family and what diseases do they cause?
- flavivirus (YFV, DFV, WNV, JE)
- pestivirus (hog cholera virus, bovine viral diarrhea - no known human pathogens)
- hepacivirus (hepatitis C)
What is the structure of the flaviviridae family?
- enveloped icosahedral virion
- env, prM and C structural proteins - M protein is cleaved from prM upon maturation of virion; C protein implicated in RNA encapsidation
True or false. The flavivirus contains linear dsRNA, a 5' capped end and a non-polyadenylated 3' end.
False, it contains linear ssRNA+.
True or false. The pestivirus has no poly-A-tail and no 5' cap.
True or false. The Hepatitis C genome is the same as the flavivirus genome.
False, the Hepatitis C genome is the same as the pestivirus genome. It has IRES (internal ribosome entry site)
Describe the lifecyle of the flavivirus.
- receptor-mediated endocytosis
- Envelope protein involved
- Dengue virus-2 interacts with glycosaminoglycans and heparin sulfate
- antibody-dependent enhancement (Dengue virus-2)
- upon entry - virion core disassembles in cytoplasm due to pH change
- C protein and ssRNA dissociates
- RNA translates viral polyprotein > cleavage into 10 mature proteins (3 structural, 7 non-structural)
- No poly-A-tail at 3' end
- 5' methylated nucleotide cap
- RNA synthesis by viral RdRp
- Encapsidation of RNA by C protein> nucleocapsid
- Viral assembly in cytoplasm and maturation of virion> accumulates within membrane boud vesicles
- transport of virus by secretory pathway
Match the following.
1. C protein
2. PrM protein
3. E protein
4. NS1 protein
5. NS2A and NS2B
7. NS4A and NS4B
A. Structural proteins
B. Non-structural proteins
C. Maturation of virion
D. Binds to cell surface receptors and facilitates viral entry
E. Encapsidates viral RNA
F. Viral protease
G. RNA replication
H. Soluble haemagglutinin - elicits humoral response
I. RNA dependent RNA polymerase
J. RNA synthesis
- 1. C protein - A. Structural proteins, E. Encapsidates viral RNA
- 2. PrM protein - A. Structural proteins, C. Maturation of virion
- 3. E protein - A. Structural proteins, D. Binds to cell surface receptors and facilitates viral entry
- 4. NS1 protein - B. Non-structural proteins, H. Soluble haemagglutinin - elicits humoral response
- 5. NS2A and NS2B - B. Non-structural proteins, J. RNA synthesis
- 6. NS3 - B. Non-structural proteins, F. Viral protease
- 7. NS4A and NS4B - B. Non-structural proteins, G. RNA replication
- 8. NS5 - B. Non-structural proteins, I. RNA dependent RNA polymerase
Match the following picornaviruses and flavivirus proteins with their functionally analogous proteins.
1. protease - L, 2A, 3C
2. RdRp - 3D
3. Capsid - VP1, VP2, VP3, VP4
C. C protein
- 1. protease - B. NS3
- 2. RdRp - A. NS5
- 3. Capsid - C. C protein
What is the etiology/pathogenesis (symptoms) of West Nile Virus?
- acquired fron mosquito (or tick) bite
- febrile, flu-like illness
- moderate to high fever
- headache, sore throat, backache, fatigue
- rash, lymphadenopathy, myalgia
- acute aseptic meningitis or encephalitis
What is the treatment for West Nile Virus?
- antiviral - Ribovarin
- mosquito control
- no vaccine
What are symptoms of Yellow fever?
- high fever
- less common: jaundice, hemorrhage, renal failures
- vaccine are available
Which human disease has the highest prevalence, but lowest mortality rate?
What are the symptoms of Dengue fever and how is it transmitted?
- lumbosacral pain
- acquired person to person via mosquitos
What is ADE (antibody-dependent enhancement)?
seen in Dengue virus, it occurs when the antibodies of one serotype enhance the virus uptake by phagocytic cells
Which Dengue fever serotype is found in America?
Is there a vaccine for Dengue fever?
What disease is the leading cause of epidemic flaviviral encephalitis in the U.S.?
St. Louis encephalitis
What are the symptoms of St. Louis encephalitis?
simple febrile headache (maybe meningoencephalitis) - mild in children, elders are at high risk
Common ways in which Hepatitis C can be transmitted:
- blood transfusions
- IV drug use
- tattooing and body piercing
What is the likely treatment for Hepatitis C infection and what is its mechanism of action? What drug can it be combined with to treat relapsed patients?
IFN treatment; induce synthesis of a set of genes that regulate viral proteins (transcription and translation); ribavirin
What 3 diseases does the togavirus cause?
- Eastern equine encephalitis
- Western equine encephalitis
- Rubella virus
What are the general characteristics of the togavirus?
- enveloped virions
- non-structural proteins (at 5' end), structural proteins (at 3' end)
- replicates in cytoplasm
What are the symptoms, route of transmission and pathogenesis of tagovirus?
fever, muscle pain, severe headache, permanent brain damage, seizures and coma; mosquito vector; hemorrhages in brain > neuronal damage
What are the general characteristics/clinical ID of the rhabdovirus?
- has glycoprotein coat and peripheral matrix protein
- ssRNA-RNA-dependent viral RNA transcriptase
- replicates in cytoplasm (as do most RNA viruses)
What is the most infectious component of the rhabdovirus?
What are some symptoms of rhabdovirus (Rabies) infection?
- difficulty breathing and swallowing
- increased muscle tone
- presence of cytoplasmic eosinophilic inclusion bodies in neuronal cells
What are the diagnostic criteria for rhabdovirus (rabies) infection?
- no single test is available
- Flourescent antibody assay
- other tests: EM, immunohistochemistry (IHC), RT-PCR
What is the post-exposure treatment for rhabdovirus (rabies)?
- local wound treatment
- passive immunity
- no specific treatment is available once symptoms of disease appear!
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