ENCEPHALITIS

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ENCEPHALITIS

VIRUSES AND THE ORAL
CAVITY
(special symptoms in the oral cavity)
semmelweis.hu/mikrobiologia
Prof. Dr. Éva Ádám D.Sc.
HERPESVIRUSES
herpein (greak) = creeping
VIRION: icosahedral capsid
(spherical), 162 capsomers,
surrounded by amorphous
tegument, lipids and
glycoproteins (peplomers) in
the envelope
EM (100-110 nm)
NUCLEIC ACID:dsDNA
REPLICATION: in the nucleus
in permissive cells: productive
infection (cytocidal, inclusion bodies)
LATENT INFECTION (genome persistance
in nucleus of neurons of lymphocytes)
3D model
CLASIFICATION OF HERPESVIRUSES
ALPHAHERPESVIRINAE
Simplexvirus
HHV-1, HHV-2 (simplex viruses)
Varicellovirus
Fast growing,
cytocidal,
latent in neurons
HHV-3 (Varicella zoster virus)
BETAHERPESVIRINAE
Cytomegalovirus
HHV-5 (Cytomegalovirus, CMV)
Roseolovirus
Slow growing,
latent in kidney,
salivary glands,
macrophages,
lymphocytes
HHV-6
GAMMAHERPESVIRINAE
Lymphocryptovirus
HHV-4 (Epstein-Barr virus, EBV)
Lymphoproliferative,
latent in B cells
DISEASES CAUSED BY HHV-1 AND -2
GINGIVOSTOMATITIS* (children)
PHARYNGOTONSILLITIS* (adults)
HERPES LABIALIS, COLD SORE** (any)
GENITAL HERPES*** (> 15 years)
KERATOCONJUNCTIVITIS*** (any)
Common, mild
Common,
mild/moderate
SKIN INFECTIONS */***(any)
Rare, moderate
ENCEPHALITIS*** (any)
NEONATAL HERPES* (newborn)
DISSEMINATED HERPES*** (any)
Rare, severe/fatal
* primer
** recurrent */*** both
Herpes labialis
Herpes genitalis
Aphthae
DIAGNOSIS: IF
CHEMOTHERAPY: acyclovir
Herpetic whitlow
Herpes gladiatorum
ECCEMA HERPETICUM
DISEASES CAUSED BY HHV-3
VARICELLA (Chicken pox)
children: rashes with or without prodromal fever and malaise
(trunk, head, limbs), ulcerating
vesicles on mucous membranes
(mouth and vulva)
adults: more severe (pneumonia)
in pregnancy: virus infects the fetus
in immunocompromised: particularly dangerous!
(disseminatation: lung, liver, brain)
DIAGNOSIS: serology (ELISA)
PREVENTION: live, attenuated
(suggested)
THERAPY: acyclovir (Zovirax)
ZOSTER (shingles) in adults
reactivation of VZV remained latent in sensory glands
vesicles:unilateral (trunk, face, are innervated by a
particular sensory glands)
complications: motor paralysis and encephalomyelitis
HERPES ZOSTER (shingles)
DISEASES CAUSED BY EPSTEINBARR VIRUS (HHV-4, EBV)
EBV infects and replicates in oropharyngeal epithelium
glandular fever (virus shedding in saliva, „kissing disease”
symptoms: sore throat, anorexia, lymphadenopathy,
splenomegaly, hepatitis
uncommon late tumors, nasopharymgeal carcinoma (Asia)
EBV infects local B cells:
restricted infection (no lysis, reactivation after transplantation: kidney)
immortalization
(indefinitive B cell proliferation): lymphoma in
immunocompromized, Burkitt´s lymphoma in Africa (cofactors: malaria, c-myc translocation)
MONONUCLEOSIS INFECTIOSA
Burkitt lymphoma Nasopharyngeal carcinoma
DISEASES CAUSED BY
CYTOMEGALTOVIRUS (HHV-5, CMV)
PRENATAL (transplacental): encephalitis, hepatitis, brain damage,
deafness, retinopathy)
PERINATAL (cervical secretions, breast milk, saliva): nil
(blood transfusion): pneumonitis, disseminated diseases
ANY AGE (saliva, sexual intercourse): mononucleosis, mild hepatitis
(blood transfusion): mononucleosis
IMMUNOCOMPROMISED (saliva, organ graft): due to reactivation
of virus, pneumonia, hepatitis, retinitis, encephalitis,
myelitis, gastrointestinal disease
DIAGNOSIS: detection of viral DNA or antigen (virus intermittently
present in urine, saliva of asymptomatic carriers), virus isolation, PCR
THERAPY: ganciclovir
Prof. Dr. Ádám Éva D.Sc.
HHV6: exanthema subitum
(roseola infantum)
- Acute febrile disease with or without
exanthems, gastrointestinal, respiratory or
CNS symptomps
 In immune suppressed patients: fulminant hepatitis
(activation of EBV, papilloma viruses and HIV
Therapy: foscarnet
HHV7: saliva, urogenital excretum (binding to CD4
receptor, therefore it is antagonistic with HIV)
HHV8: Kaposi sarcoma
(malignancy)
Kaposi Móric (hungarian
dermatocologist)
- classic form, endemic in Afrika)
- AIDS
1872.
Less than 10/10000 man
More than 10/10000 man
MUMPS (parotitis epidemica)
Disease: non purulent disease of the lymphoid tissues
Latency: 2 to 3 weeks (fever,
vomiting, nausea)
Complication: orchitis (pancreatitis, neuritis
(VIII. cranial nerve
deafness)
PREVENTION: attenuated
mumps virus (MMR))
Routine immunization against mumps
One dose
Repeated
(two doses)
(two doses)
no immunization
MEASLES (MORBILLI)
Spread: respiratory droplets: (latency 10 days)
Replication in the cells of mucous membrane of respiratory tract
Primary viremia (local lymph tissues)
Infected lymphocytes
Secunder viremia (in all cells, giant cell
formation)
KOPLIK’ spots (on the mucous
membrane of the mouths),
rashes all over the body
long lasting immune reaction
(reversible negativity of the
type IV.allergic reaction)
Koplik’ spots
CONTROL:
attenuated virus
(MMR)
POSSIBLE OUTCOMES OF
MEASLES
Problems with
cellular immunity
Problems with Ig
formation
severe, life-danger
Normal outcome
Complications: pneumonia, encephalitis
SSPE (Subacute sclerotizing panencephalitis)
DIAGNOSIS: clinical symptoms, serology (HAG, ELISA)
PICORNA VIRUSES
Herpangina (Coxsackie A virus)
)
„Hand-foot-and-mouth disease”
(coxsackie A16 virus)
ARBO- and ROBOVIRUSES
Families
FLAVI-
Genera
Flavi- (Hepaci- :Hepatitis C)
TOGA-
Alpha- (Rubi-: rubellavirus)
BUNYA-
Bunya-, Phlebo-, Nairo- Hanta-
REO-
Colti-, Orthoreo-, Rota-
ARENA-
„Old World”-, „New world”-
FILO-
Marburg-like and Ebola-like
arbo: blood suckling vectors, robo: human and animal /rodent/
viruses (without vector), obligate human pathogens, human and
animal pathogens (enterally transmitted)
1. Encephalitis
2. Haemorrhagic fever with or without
hepatitis
3. Fever, muscle and joint pains,
rashes
FLAVIVIRUSES
Flavus: yellow
40-50 nm, cubical, ss(+) RNA genom, envelope
with glycoprotein projections:
haemagglutination
Immaturated
virion
Maturated
virion
• protease resistant
• replication insects (vector) and in human being
(no disease in natural hosts:rodents,birds)
• in vector: virus replication in the gut and other
organs, presence in saliva (only female vectors are
„infectious”, transovarial transmission!)
Nucleoprotein
• vertebrates are infected by vectors only in the case of high titer of
virus
• final host: human being/horse (low titer in blood, not enough to
infect the vectors)
TRANSMISSION and
PATHOGENESIS OF
FLAVIVIRUSES
gerincesek
moszkitó
vírus
vírus
Inapparent infection
Encephalitis (St. Louis encephalitis)
Hemorrhagic fever, nephritis,
hepatitis (Yellow fever)
Hemorrhagic fever (Dengue)
Fever with rashes (Dengue, West Nile
encephalitis)
kullancs
Flu-like symptoms
increased vascular permeability
(antigen-antibody complexes:
complement activation, vasoactive
amins, DIC), bone marrow destructions
YELLOW FEVER
Main symptoms: fever, head- and muscle pain, photophobia, than kidney- and liver
destruction (jaundice, albuminuria, haematemesis, blood in feaces
and other haemorrhagies), 10-40% mortallity
Jungle yellow fever : monkeys (reservoir)
human
Haemagogus mosquito
Urban yellow fever: human (reservoir)
human (vaccination)
Aedes aegypti
PREVALENCE OF
YELLOW FEVER VIRUS
HIGH
RISK
17. sz. Mexico
1881. Finlay, C.: transmission by mosquito
1901. Reed, W.: demonstration of virus
origin
Control (1939): Theiler 17D vaccine,
(attenuated virus), obligatory in
international travelling
Theiler, Max
(1899-1972)
Medical/
Physiological Nobel
Prize, 1951
IMMUNITY: life long
1905. Panamachannel, caranteen
DIAGNOSIS: in special labs (biosafety BSL-IV),
RT-PCR
Serology: ELISA, direct IF
DENGUE (Breakbone-fever)
Vector: Aedes aegypti
Classic dengue-fever (rarely life threatening): flu-like symptoms (fever, head-,
muscle- and joint pains, enlarged lymphnodes), maculopapular rashes, leukopenia
(world-wide)
Dengue virus infected Aedes aegypti
Epidemy caused by Aedes aegypti and Dengue
Dengue haemorrhagic fever (10 % mortality): at the begining similar to classic
form, than shock and haemorrhages (gastrointestinal tract and skin, Asia), in secondary
infection, cross-reacting antibodies activate the complement system, increased vascular
permeability
Antiviral chemotherapy: NO
Vaccine: NO
WEST NILE encephalitis
- first desciption: Uganda, Culex species
- central nervous system, lymphadenopathy in elderly patients
Epidemics (human)
Epidemics (horses)
1994. Algeria
1996-1997. Roumania
1997. Czech Rep.
1998. Congo Dem. Rep.
1999. Russia
1999-2000. USA
2000. Israel
2002. USA
1996. Morocco
1998. Italy
1999-2000. USA
2000. France
Climate changes, increasing number of
vectors
Spring-summer meningoencephalitis
(central european encephalitis, „louping ill”)
•
•
•
•
•
•
Reservoirs: small rodents, goats
Vectors: Ixodes and Dermacentor spp. (ticks)
Pathogenesis: (1) viraemia, (2) flu-like symptoms, (3) CNS
manifestation  aseptic meningoencephalitis
Immunity: life long, humoral and cellular
Diagnosis
– Anamnestic data (tick-bite)
– Serology
• blood, CSF
• ELISA IgM, IgG
Treatment: symptomatic
Endemic areas in
Europe
Control: active immunization (inactivated
vaccine)
Encepur Junior (1-12 years): basic
immunization, 3 injection,
repetition in every 3 years
Encepur Adult ( 12 years) ,
FMSE-Immun (adults and children)
passive immunization (post exposure prophylaxis)
TOGAVIRUSES
Toga (dress in the ancient Rome): enveloped virus
70 nm, cubical, ss(+) RNA
• in the envelop: projections
(haemagglutination)
• protease sensitive
• reservoirs: birds, rodents and other
vertebrates
Febrile disease with encephalitis (Eastern-,
Western-, Venezuelan horse (equine)
encephalitis)
Febrile disease with rashes and arthralgia ( Ross
River, Sindbis, O’ nyong -nyong, Chikungunya)
Control: immunization of horses with inactivated
(Eastern- and Western horse encephalitis), or
attenuated (Venezuelan horse encephalitis) vaccine
ARENAVIRUSES
(„Old-World”- and „New-World”
arenaviruses)
Arena: sandy
ribosome granules of host cell origin, „sandy”
• roundish, pleomorphic, enveloped viruses
with 10 nm projections
• two ss (+) RNA
• natural hosts: rodents
LYMPHOCYTIC CHORIOMENINGITIS VIRUS (LCM): in mouse latent
infection, in other species (in human too) fatal meningitis
Spread: with biting of mouse or with infected feaces (eating of infected
foods, or inhalation)
Pathogenesis:
dependent on the age of animal and mode of transmission
(transovarial), inhibition of the cellular immune response: no
acute reaction (disease)
Tacaribe complex: Junin haemorrhagic fever (Argentina, reservoir:
mouse): humoral and cellullar immune
suppression
Machupo haemorrhagic fever (Bolivia, reservoir:
mouse)
Lassa virus (haemorrhagic fever)
/Niger, Lassa 1969/
- natural host: rat (direct contact,
skin)
- symptoms: fever, head ache, vomiting,
diarrhoea, lung, heart, kidney and brain
problems, haemorrhages)
- endemic areas: asymptomatic
- ribavirin (antiviral chemotherapy) :
decrease of number of death
-
BUNYAVIRUSES
Enveloped, spherical, 80-100 nm, helical viruses
• three, different, circular (-) RNA
• glycoprotein projection
• replication in vertebrates and in vectors too
(vectors: mosquito and tick)
Rezervoirs:
mouse or rat (persistent infection),
transmission with the excretions
of animals
No human-human transmission
Diagnosis
in BSL-III, BSL-IV laboratories
Virus isolation
Serology: ELISA
PATHOGENESIS OF HANTAAN
VIRUS INFECTION
Infected feces
become
airborne
Virus
contained
rodent feces
Acute
respiratory
distress
Inhalation of
feces by human
Symptoms:
muscle aches,
fever,
headache,
cough
EMERGING VIRUSES
FILOVIRUSES
Helical nucleocapsid, filamentous (about 14.000 nm)
MARBURG VIRUS (haemorrhagic fever),
1967.Germany (Marburg), Yugoslavia: monkeys
(labs)
transmission: direct contacts, body fluids,
respiratory droplets infected monkeys
(working with)
symptoms: fever, letargy, rashes, diarrhoea, neurological, haemorrhagies
letality: 25-30%
diagnosis: difficult, virus in liver, semen (12 week)
therapy-control: NO
EBOLA VIRUS (haemorrhagic fever)
incubation: 2-21 days
transmission: direct contact with blood, body fluids, organs of infected
patiens, burial ceremonies (direct contact with deceased
person), nurses, physicians in hospitals, infected animals
History of
EBOLA
2014
Symptoms of Ebola virus infection
Diagnosis: special laboratories (BSL-IV.)
in special dress
Therapy : rehydration
Control: NO vaccine
Moving of Ebola patient
VIRION MORPHOLOGY: bullet shaped, helical nucleocapsid,
glycoprotein peplomers (neutralizing ab.), matrix protein
under lipoprotein envelope (plasma membrane)
:
NUCLEIC ACID: ss (-) RNA
CLASSIFICATION of RHABDOVIRUSES
Family: RHABDOVIRIDAE
Genera: VESICULOVIRUS
Vesicular stomatitis virus (VSV)
LYSSAVIRUS (7 serotypes - 1 classic)
RABIES VIRUS
„street virus” (wilde virus): long and variable incubation period
(sensitive animal: : wilde carnivores (foxes), dogs, cats and cattle!
rezervoirs: vampire bats)
„Fix’” virus: stable, short incubation period
5-7 days before onset the virus is
present in the saliva of the
animals!
infection
Transmission
from wilde to
domesticated
animals
Negri testek
Negri bodies
Virus entry via bite (or
aerosol, inhalation)
disease
Pathogenesis of rabies
Incubation period:
from 5 days, to 2
years
Periferial
neurons
Salivary
glands
RABIES
SILVAN rabies: in wild animals
URBAN rabies: domesticated animals (cats, dogs, and others
/cattle/, etc.)
Infection: biting, scratch (saliva!) enteral (infected milk, cattle),
human-human transmission: only with transplantation!
PHASES and SYMPTOMS OF RABIES
 prodromal phase (malaise, vomiting, sore throat, paresthesia at
site of bite)
 sensory phase (sympathetic overactivity, salivation, perspiration,
spasm of the throat muscle: hydrophobia
 excitement
 paralytic or depressive    death
fertőzés
fertőzé
s
Rabies
vírus
hydrophobia
excitement
Akut idegrendszeri
szakasz
(2-7 nap)
Kóma (5-14
nap)
salivation
„dumb” rabies
(vampire bat)
rabies
rabies free
no information
Number of human
rabies death
0
1-10
10-100
100-1000
1000-10000
10000
no data
VACCINES AGAINST RABIES
First vaccine against
rabies from „aged”
spinal cord of dogs
infected with rabies
virus (1885)
Louis PASTEUR
Pre-exposure vaccination
animals (dogs, cats – inaktivated virus)
man (occupational risk - inactivated virus)
Post-exposure vaccination
inactivated virus produced on human
diploid cell culture
RECOMBINANT DNA TECHNOLOGY: in live
vaccinia virus, major protective antigen
„G” glycoprotein (oral administration in
wild animals)
Endre
HŐGYES
(1847-1906)
Indications of post-exposure vaccination
DOG, CAT
healthy, observable for 14 days
Nothing to do
Animal with suspected rabies or the
suspicion of rabies cannot be
excluded
FOX
Complete
vaccination
Non observable
Complete vaccination
regard as rabid
Complete vaccination
Other animals
If the suspicion of rabies
cannot be excuded
Complete
vaccination
Vaccination on the 0., 3., 7., 14., 30. and 90. day
SLOW VIRUSES
DISEASES CAUSED BY
SUBVIRAL ELEMENTS
VIRUSES
 measles virus (Subacut Sclerotizing Panencephalitis, SSPE)
 rubella virus (progressive panencephalitis, congenital rubella)
 papova viruses (JC, BK, progressive multifocal leukoencephalopathia)
 HIV (AIDS dementia complex)
 picorna viruses (persistant enterovirus infections in immunodeficient
patients)
SUBVIRAL AGENTS (prions)
Subacut spongioformis encephalopathia
Human diseases
Animal diseases
Creutzfeld-Jacob disease
Gerstmans, Straussler, Scheinker
disease
Fatal familiar insomnia
Scrapie
Bovine Spongioform encephatopathy
Transmissible mink encephalopathy
Kuru
The prion is dangerous because it
promotes refolding of native proteins into
the diseased state
(Step-1 : UNFOLDING of alpha-helices;
Step-2 : REFOLDING to beta-pleated
sheets)
PRION DISEASES (animals)
- Scrapie (sheep, goat)
- Transmissible mink encephalopathia (TME),
chronic „wasting disease”
(CVD: deer, moose elk)
- Bovine Spongioformis Encephalopathy (BSE: cattle)
PRION DISEASES (human)
- Creutzfeld-Jacob disease (CJD, sporadic form,
1920): in elderly patients (60 years), dementia,
ataxia, coma, death (6 month),
Acquired forms: 1. iatrogenic CJD cases (contaminated
surgical tools, from cadaver growth and other hormones)
2. vCJD (v=variant) from BSE infected cattles
- Gerstmans, Straussler, Scheinker (GSS,
1936): around 50 years old patients,
cerebellar ataxia, slow progression
(about 5 years)
- Fatalis familiar insomnia (1986)
Symptoms: spongioformis encephalopathia, dementia, pyramidal,
extrapyramidalis dysfunction
Epidemiology: meat, kannibalism (kuru), JC (familiar), BSE (infectious?),
nosocomial (hypophysis hormone, cornea transplantation)
Treatment: symptomatic (death in a few months)
Prevention: avoid fodder of animal origin, burning of animal cadavers,
drugs (hormones, controlled), avoid of eating of animal brain,
transplantation etc.
Decontamination: 2N NaOH (1 hour), 1N NaOH (2 hours) combined with
autoclaving (134C, 1 hour)
Prusiner, S. B.
Nobel Prize, 1997
(prions)
Kuru (1950): cerebellar ataxia, dementia
Gajdusek , B. C. (Nobel Prize 1976)
„laughing death”

ENCEPHALITIS

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