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a Virology 09 vervous 1


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Arthropod-Borne Encephalitis Viruses
- from inf birds/rodents to humans via mosquito bite
- must replicate in mosquito gut then move to salivary gland prior to transmissions
- peak is mid to late summer
- no human to human spread
- human viremias insufficient to let humans be the reservoir
- Alphavirus genus of the family Togaviridae and the Flaviviridae family
Alphaviruses Types
- *Eastern Equine Encephalitis (EEE)*
- Western Equine Encephalitis (WEE)
- Venezuelan Equine Encephalitis (VEE)
Flaviviruses Types
- *St. Louis Encephalitis (SLE)*
- Japanese Encephalitis (JE)
- Tick-Borne Encephalitis (TBE)
- West Nile virus
- Dengue virus
Alphavirus Structure and Replication
- Togaviridae family
- (+) sense ssRNA
- Icosahedral nucleocapsid(1 capsid protein)
- envelope w/ 2 viral prots(M and E)
- Replication in cytoplasm with budding at PM
Alphavirus Epi (EEE)
- wild birds resivour(amplifying host)
- mosquito persistently infected
- along eastern seaboard
- only a few cases a year, only 2% is Ab + in epidemics
- Aedes albopictus, “Asian tiger mosquito”, is new
- might let virus be a bigger problem, since it can feeds on birds and humans
- human-to-human in aerosol in lab
Alphavirus Clinical Features
- Most subclinical effected by:
a)manner of inoculation
b)non-specific immunity(old/kids=more effect)
c)diff in host immunity(degree of immune-mediated damage)
d)strain differences among viruses
- febrile illness, may lead to encephalitis (50-75% fatal)
- 10-12 day febrile illness, then fever, stiff neck, loss of consciousness
- may go to seizures, coma and death or it may resolve
Alphavirus Pathogensis
- moves from the blood ⇒ endothelial cells ⇒ nerve cells
- symptoms from viral action on nerve cells and host imflam response
- EEE is cytolytic(inf-induced apoptosis)
- IFNs important
Alphavirus Treatment and Diagnosis
- recovery due to development of Ab to envelope glycoproteins
- diagnosed by presentation or w/ serological tests like IgM ELISA
- No vaccine or treatment
Flaviviruses Structure and Replication
- Flaviviridae family, like HCV
- can cause yellow fever
- (+) sense ssRNA
- Icosahedral nucleocapsid w/ 1 capsid protein w/ envelope (M and E)
- Replication in cytoplasm with budding at internal membranes
Alphaviruses Immunity
- Protective humoral immunity directed to envelope proteins
- CTLs do inflam response
Flaviviruses Immunity
- Protective humoral immunity directed to envelope proteins
- CTLs do inflam response
St. Louis Encephalitis Virus Clinical Features
- most prevalent arthropod encephalitis viruses in US
- most subclinical
- may begin w/ fever, malaise, headache, drowsiness -> encephalitis, meningitis, & febrile headache
- elderly=10x more likely to die than young, have more severe symptoms often complicated by pre-existing conditions
SLE Virus Epi
- maintained in mosquitoes in winter reservoirs in North Am
- transmission begins in spring/early summer w/ birds as amplifying host
- human disease peaks from July - Sept
- 50/year in US
- 5-15 year outbreak cycles
St. Louis Encephalitis Virus Diagnosis
- consider if encephalitis, meningitis or febrile headache in July-September, esp old
- PCR of blood, CSF or tissue
- IgM in serum or CSF by ELISA
- Ab testing of paired(acute/convalescent) sera
- immunofluor for SLE Ag in cells of urine sediment or CSF
St. Louis Encephalitis Virus Treatment and prevention
- no vaccine, treatment limited to supportive therapy
- reduce of vector populations
- hard to do since expansion of mosquito habitat, insecticide resistance, new vectors species, reduction in mosquito control programs
West Nile Virus
- severe meningoencephalitis in elderly in israel
- came to US in 1999(plane), found in wild birds, horses and humans
- 2002 outbreak, most cases from mosquito bite, some from transplants
- blood is now screened
- usually in old
- if pregnant, rarely associated with spontaneous abortion and neonatal illness, but not birth defects
- but intrauterine infection possible
The Picornaviridae family
1)Genus Enterovirus:
a) poliomyelitis virus
b) echoviruses (enteric cytopathic human orphan virus)
c) enteroviruses
d) coxsackieviruses (Coxsackie, NY …site of first isolation)
2)Genus Rhinovirus (including “cold” viruses)
3)Genus Hepatovirus (hepatitis A virus)
Poliomyelitis Structure
- small, (+) ssRNA
- spherical, icosahedral, acid stable(suvive at pH 3 or lower)
- 3' poly (A) tail and a 5’ VPg
- NTRs flank coding regions
Poliomyelitis Replication
- initially replicates in the human intestinal tract
- attaches to receptors (which determine tropism)
- viropexis(Receptor mediated Endocyt) does penetration and uncoating(energy-dependant)
- translation is cap-independent
- cap-binding complex (CBC) shuts of host proteins
- uses RNAdependentRNA polymerase
- asymmetric, many (+) molecules made few (-)
Poliomyelitis Clinical Features
- most subclinical(99%)
- malaise, fever, headache, nausea(only last a few days->"abortive poliomyelitis"
- rarely can cause aseptic meningitis (resolves in 2-10 days)
- rarely, paralytic polio
- most significant paralysis presents w/in a few days, and most recovery is w/in 6 months
- “progressive post-poliomyelitis muscle atrophy” - 25-40% have additional deterioration decades later from effects of aging
Poliomyelitis Pathogenesis
- alimentary tract via mouth
- shed in feces for several weeks
- 1o replication in OP mucosa, tonsils, LNs
- ingested to gut and adjacent lymphoid tissue
- 1o viremia from infection of Peyer's patches and mesenteric LNs
- spread to SC, meninges, and muscle
- paralysis after 10 days from: direct destruction of the neurons or edema-induced damage of the neurons (reversible)
- fatal outcome if infection gets the CV and Resp centers of the medulla oblongata
Poliomyelitis Epidemiology
- poliomyelitis not endemic (unlike other enteros) b/c of vaccination
- bad(endemic) in Sub-Saharan Africa and South Asia
- in US, only in immunocompromised vaccinees, imports, vaccinated contact
Non-poliomyelitis enteroviruses Epidemiology (NPEV)
- usually no pandemic, just periodic sweeping every few years
- most mild or asymptomatic
- usually in kids in summer
- lower socioeconomic areas
- often found shellfish harvesting water
Poliomyelitis Diagnosis
- clinical signs nondescript, unless combined w/ knowledge of a current epidemic
- specific viruses identified via immuno-serological techniques
- appropriate specimens are stools, rectal and throat swabs
- mixed infections of enteroviruses are not common
Poliomyelitis Prevention and Treatment
- vaccination is key (but none for other enteroviruses)
- isolation of infected
- resistant to disinfectants
Poliomyelitis Killed(Salk, IPV) vaccine advantages
- can be combined w/ (DPT)
- no mutation
- ok if immunodeficient
- reduces spread of live polioviruses
Poliomyelitis Killed(Salk, IPV) vaccine disadvantages
- low % develop Abs, so repeated boosters needed
- no intestinal immunity
- expensive
Poliomyelitis Live(Sabin, OPV) polio vaccine advantages
- humoral and intestinal immunity (like natural)
- immunity lifelong
- oral, works quickly
- relatively inexpensive
- uses of continued cell lines, no contaminants
Poliomyelitis Live(Sabin, OPV) vaccine disadvantages
- may mutate -> neurovirulence
- spreads to other persons and environment
- problem if immunodeficient
- monkey testing
Polyomaviruses JC virus
- PML, a progressively fatal, neurodegenerative disease
- due to SV 40 ('the vacuolating agent')
– maybe from contaminated OPV vaccine
- Inclusion bodies seen in brain
- 1-10% of AIDS patients
Polyomaviruses BK virus
- isolated from urine of pt after renal transplant
- in 50% of patients after bone marrow transplantation
- distantly related to SV 40
Polyomaviruses Structure
- Papovavirus family
- naked, icosahedral virions
- circular dsDNA
- from SV40
- in 40% of tumors in non-Hodgkins lymphomas and brain and bone tumors and mesotheliomas
– contaminated polio vaccine?
Polyomaviruses Replication
- replicate in nucleus
- do NOT encode a viral DNA dependent DNA polymerase;
- use host DNA dependent DNA polymerase for genome replication
- uses host DNA dependent RNA polymerase II for transcription
- progeny virions assemble in cell nucleus
Polyomaviruses Pathogenesis
- only in immunosuppressed -> inapparent, cryptic infection
- transmitted via respiratory route
- host cells are killed by viral cytolytic infection
- cannot manifest transformation phenomenon
- can be transformed to neoplastic growth in non-natural cells
Herpesviridae family
- herpes simplex (HSV)
- varicella zoster virus (VZV)
- cytomegalovirus (CMV)
- Epstein-Barr virus (EBV)
- HHV 6 and HHV 7 (roseola)
- HHV 8 (Kaposi sarcoma associated virus)
- monkey B virus (serious neurotropic virus for humans)
HSV-1 Clinical Features
1)Primary Disease usually asymptomatic (esp if < 10yr)
- if symptoms, gingivostomatitis, with vesicular eruptions on mouth -> ulcerative lesions
- 2-3 weeks
2)latent infection in sensory neurons then reactivated disease from stress
- prior to episode, often altered sensation of area(pain,itch,tingle) then vesicls 1-2 days later
– fewer lesions than 1o and on mucocutaneous borders
- asymptomatic shedding common
HSV-2 Clinical Features
1)Primary Disease usually symptomatic
- painful, vesicular lesions on the genitals -> pustules and ulcers
- systemic infection common
2)reactivated Disease is milder
- If 1o was severe, recurrences more frequent
- asymptomatic shedding common
HSV in Pregnancy Clinical Features
- vertical transmission of HSV-2 during delivery (asymptomatic shedding)
- recurrent disease is much less risky because of the reduced shedding of the virus
- in utero cases systemic, with high mortality
HSV Acute Necrotizing Encephalitis
- HSV=most common cause, high mortality, sporadic encephalitis
- usually in immunocompromised
Herpes simplex Keratoconjunctivitis
- second to trauma as a cause of corneal blindness in the U.S.
HSV Structure
- large dsDNA
- icosahedral capsid surrounded by the tegument in envelope
HSV Replication
- in nucleus
- transcription by host DNA dependent RNA polymerase II
- replication by virus-coded DNA dependent DNA polymerase
- envelope and maturation in cytoplasm
HSV Pathogenesis
- invades epi -> multinucleate giant cells
- released via exocytosis and cell necrosis
- main pathogenic effect is cell lysis:
1)leaks vesicular fluid between the dermis and epidermis->creating the vesicle->facilitates spread
- HSV-1 universal, usually before 5
- spread by direct contact with lesions or secretions
- asymptomatic kids are major HSV-1 source
- no animal vectors or seasonal patterns
- sex is HSV-2 source
– 20% of females shed asymptomatically
HSV Diagnosis
- history and vesicular lesions
- characteristic CPE in tissue culture
- in herpes encephalitis, PCR of the CSF
HSV Treatment
- no vaccine for either form is yet licensed
- acyclovir (Zovirexâ„¢), a nucleoside analog
– only active in virus-infected cells -> chain termination
- can become resistant from mutations of viral TK that don’t accept ACV
- fortunately, acyclovir resistant mutants are avirulent
- a new subunit vaccine of HSV-2 envelope D is in trial

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