Transcript RNA Viruses

RNA Viruses
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M.Tvorko
RNA Viruses
• Diverse group of microbes
• Assigned to one of 12 families based on
envelope, capsid, and nature of RNA
genome
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Enveloped Segmented
Single-Stranded RNA Viruses
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The Biology of Orthomyxoviruses:
Influenza
• 3 distinct influenza virus types: A, B, C; Type
A causes most infections
• Viral infection
– Virus attaches to, and multiplies in, the cells of the
respiratory tract
– Segments of RNA genome enter the nucleus
(transcribed/translated)
– Finished viruses are assembled and budded off the
cell with an envelope
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ОRTHOMYXOVIRUSES
HA - hemagglutinin
NA - neuraminidaze
helical nucleocapsid (RNA minus
NP protein
Bilayer lipid membrane
polymerase complex
M1 protein
types A, B, C : NP, M1 protein
subtypes: HA or NA
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• Key to influenza are glycoprotein spikes –
– Hemagglutinin (H) – 15 different subtypes; most
important virulence factor; binds to host cells
– Neuraminidase (N) – 9 subtypes – hydrolyzes
mucus and assists viral budding and release
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Hemagglutinin (HA)
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Influenza virus cycle
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Influenza A
• In Birds
– 16 HA A variants
– 9 NA A variants
• In Humans
– 3 HA A variants
• (H1, H2, and H3)
– 2 NA A variants
• (N1 and N2
• Both glycoproteins frequently undergo genetic
changes decreasing the effectiveness of the host
immune response
• Constant mutation is called antigenic drift – gradually
change their amino acid composition
• Antigenic shift – one of the genes or RNA strands is
substituted with a gene or strand from another
influenza virus from a different animal host
– Genome of virus consists of 10 genes encoded on 8 separate
RNA strands
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Antigenic
shift event
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Influenza B
• Only undergo antigenic drift
• Not known to undergo antigenic shift
Influenza C
• Known to cause only minor respiratory
disease; probably not involved in epidemics
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Influenza A
• Acute, highly contagious respiratory illness
• Seasonal, pandemics; among top 10 causes of death in
U.S. – most commonly among elderly and small
children
• Binds to ciliated cells of respiratory mucosa
• Causes rapid shedding of cells, stripping the
respiratory epithelium; severe inflammation
• Fever, headache, myalgia, pharyngeal pain, shortness
of breath, coughing
• Weakened host defenses predispose patients to
secondary bacterial infections, especially pneumonia
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Diagnosis, Treatment, Prevention
• Rapid immunofluorescence tests to detect
antigens in a pharyngeal specimen; serological
testing to screen for antibody titer
• Treatment: control symptoms; amantadine,
rimantadine, zanamivir (Relenza), and
oseltamivir (Tamiflu)
• Flu virus has developed high rate of resistance
to amantadine and rimantadine
• Annual trivalent vaccine recommended
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Influenza Vaccines
• Whole virus vaccine: inactivated virus vaccine grown in
embryonated eggs; 70-90% effective in healthy persons
<65 years of age, 30-70% in persons ≥65 years
• Split virus vaccine: previously associated with fewer
systemic reactions among the elderly and children <12
years
• Subunit vaccine: composed of HA and NA
• Live, attenutated influenza virus vaccines under
development
Enveloped Nonsegmented ssRNA Viruses
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Paramyxoviruses
Paramyxoviruses (parainfluenza, mumps virus)
Morbillivirus (measles virus)
Pneumovirus (respiratory syncytia virus)
• Respiratory transmission
• Envelope has glycoprotein and F spikes that
initiate cell-to-cell fusion
• Fusion with neighboring cells – syncytium or
multinucleate giant cells form
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PARAMYXOVIRUSES
• HN/H/G glycoprotein
F glycoprotein
SPIKES
helical nucleocapsid (RNA minus
NP protein)
polymerase complex
M protein
The effects of paramyxoviruses
Insert figure 25.5
Effects of paramyxoviruses
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Parainfluenza
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Widespread as influenza but more benign
Respiratory transmission
Seen mostly in children
Minor cold, bronchitis, bronchopneumonia,
croup
• No specific treatment available; supportive
therapy
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Mumps
• Epidemic parotitis; self-limited, associated with
painful swelling of parotid salivary glands
• Humans are the only reservoir
• 40% of infections are subclinical; long-term immunity
• 300 cases in U.S./year
• Incubation 2-3 weeks fever, muscle pain and malaise,
classic swelling of one or both cheeks
• Usually uncomplicated invasion of other organs; in
20-30% of infected adult males, epididymis and testes
become infected; sterility is rare
• Symptomatic treatment
• Live attenuated vaccine MMR
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Mumps
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Measles
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Caused by Morbillivirus
Also known as red measles and rubeola
Different from German measles
Very contagious; transmitted by respiratory
aerosols
Humans are the only reservoir
Less than 100 cases/yr in U.S.; frequent cause of
death worldwide
Virus invades respiratory tract
Sore throat, dry cough, headache, conjunctivitis,
lymphadenitis, fever, Koplik spots – oral lesions
Exanthem
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Signs and symptoms of measles
Measles
• Most serious complication is subacute sclerosing
panencephalitis (SSPE), a progressive
neurological degeneration of the cerebral cortex,
white matter, and brain stem
– 1 case in a million infections
– Involves a defective virus spreading through the brain
by cell fusion and destroys cells
– Leads to coma and death in months or years
• Attenuated viral vaccine MMR
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RESPIRATORY SYNCYTIAL (RS)
VIRUS
It is the single most serious cause of bronchiolitis
and pneumonitis in infants.
The particle is slightly smaller (80-120 nm) than other
paramyxoviruses, and the nucleocapsid measures 1115 nm. Although RS is one of the most labile of
viruses. RS virus does not hemagglutinate.
RSV Bronchiolitis- clinical
features
Symptoms for this disease
are:
sneezing
runny nose
sore throat
low fever
common cold symptoms just
more severe.
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RSV is a viral disease.
Respiratory Syncytial Virus (RSV)is
a very serious virus often found in
children and infants under the age of three.
Adults are at very low risk of catching RSV.
Rabies
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Rhabdovirus family; genus Lyssavirus
Enveloped, bullet-shaped virions
Slow, progressive zoonotic disease
Primary reservoirs are wild mammals; it can be
spread by both wild and domestic mammals by bites,
scratches, and inhalation of droplets
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Structure of the rabies virus
Insert figure 25.8
Structure of rabies virus
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Rabies
• Virus enters through bite, grows at trauma site for a
week and multiplies, then enters nerve endings and
advances toward the ganglia, spinal cord and brain
• Infection cycle completed when virus replicates in the
salivary glands
Clinical phases of rabies:
• Prodromal phase – fever, nausea, vomiting, headache,
fatigue; some experience pain, burning, tingling
sensations at site of wound
• Furious phase – agitation, disorientation, seizures,
twitching, hydrophobia
• Dumb phase – paralyzed, disoriented, stuporous
• Progress to coma phase, resulting in death
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Pathologic pictures of rabies
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• Often diagnosed at autopsy – intracellular inclusions
(Negri bodies) in nervous tissue
• Bite from wild or stray animals demands assessment
of the animal, meticulous wound care, and specific
treatment
• Preventive therapy initiated if signs of rabies appear
• Treatment – passive and active post exposure
immunization
– Infuse the wound with human rabies immune globulin
(HRIG) and globulin; vaccination with human diploid cell
vaccine (HDCV), an inactivated vaccine given in 6 doses
with 2 boosters
• Control – vaccination of domestic animals,
elimination of strays, and strict quarantine practices
– Live oral vaccine incorporated into bait for wild animals
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Arboviruses
• viruses that spread by
arthropod vectors
– mosquitoes, ticks,
flies, & gnats
• 400 viruses
The Influence of the Vector
• Vectors and viruses tend to be clustered in the tropics
and subtropics
– many temperate zones have periodic epidemics
• life cycles are closely tied to the ecology of the vectors
• peak incidence when the arthropod is actively feeding
and reproducing
• Humans can serve as dead-end, accidental hosts or
they can be a maintenance reservoir
• Controlling the vector controls the disease
Characteristics of Arbovirus Infections
• Viral encephalitis
– brain, meninges, and spinal cord are involved
– convulsions, tremor, paralysis, loss of coordination, memory
deficits, changes in speech and personality, coma
– survivors may experience permanent brain damage
• Treatment is supportive
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Togaviruses
• Enveloped virion containing non-segmented, ssRNA (both
+ an – sense) ~11.7kb
• Subspecies (i.e.: Rubella virus) causes Rubella or German
Measles
• Symptoms include low grade fever,
sore throat, rash, and lymphoadenopathy
• Viral RNA is complimented by the host cells machinery and
the –’ve sense strand produced serves as a template for
more +’ve sense strands
Rubella
• Caused by Rubivirus, a
Togavirus
• ssRNA with a loose
envelope
• German measles
• Endemic disease
• Most cases reported are
adolescents and young adults
• Transmitted through contact
with respiratory secretions
Rubella
Two clinical forms:
• Postnatal rubella
– generally mild
– malaise, fever, sore throat, lymphadenopathy, rash
– lasting about 3 days
• Congenital rubella
– infection during 1st trimester most likely to induce
miscarriage or multiple defects
• Diagnosis based on serological testing
• No specific treatment available
• Attenuated viral vaccine MMR
Hemorrhagic Fevers
Yellow fever
eliminated in U.S.
– Two patterns of transmission:
• urban cycle
– humans and mosquitoes
• sylvan cycle
– forest monkeys and mosquitoes
– South America
– Acute fever, headache, muscle pain
• may progress to oral hemorrhage, nosebleed, vomiting, jaundice, and
liver and kidney damage
– significant mortality rate
Hemorrhagic Fevers
Dengue fever
flavivirus carried by Aedes
mosquito
usually mild infection
– dengue hemorrhagic shock
syndrome, breakbone fever
• extreme muscle and joint pain
• can be fatal
Bunyavirus
• Spread by infected
animals
• Hantavirus pulmonary
syndrome (HPS)
– caused by a strain of
hantavirus named “Sin
Nombre”
– deer mouse is the host
• sheds the virus in saliva,
urine, and feces
Model of Human Hepatitis C Virus
Lipid Envelope
Capsid Protein
Nucleic Acid
Envelope Glycoprotein E2
Envelope Glycoprotein E1
HCV - Epidemiology
Prevalence In Groups at Risk
Recipients of clotting factors before 1987
75 - 90%
Injection drug users
70 - 85%
Long-term hemodialysis patients
10%
Individuals with > 50 sexual partners
10%
Recipients of blood prior to 1990
5%
Infants born to infected mothers
5%
Long-term sexual partners of HCV positive
1 - 5%
Health workers after random needlesticks
1 - 2%
HCV
• ACCOUNTS FOR 90-95% OF POST
TRANSFUSION HEPATITIS
• RISK OF SEXUAL TRANSMISSION
LOWER THAN FOR HBV
• RISK THROUGH CASUAL CONTACT
LOW
HCV
• VERTICAL TRANSMISSION
POSSIBLE
– RISK INCREASED IF MOTHER IS
POSITIVE FOR HCV RNA
– RISK INCREASED IF MOTHER IS HIV
POSITIVE
• OVERALL PREVALENCE
ESTIMATED
AT 1.4%
WHO IS AT GREATEST RISK FOR
HCV INFECTION?
• DRUG ABUSERS
• BLOOD PRODUCT RECIPIENTS (ANTI-HCV
SCREENING HAS GREATLY REDUCED
RISK)
• HEMODIALYSIS PATIENTS
• LAB PERSONNEL WORKING WITH BLOOD
PRODUCTS
WHO IS AT GREATEST RISK FOR
HCV INFECTION?
• SEXUALLY ACTIVE HOMOSEXUALS
• PERSONS WITH MULTIPLE AND
FREQUENT SEXUAL CONTACTS
• MEDICAL/DENTAL PERSONNEL (3-10%
VIA NEEDLESTICK FROM INFECTED
PATIENT)
HDV INFECTION PATTERNS
COINFECTION
ACUTE SIMULTANEOUS
INFECTION WITH HBV AND HDV
OFTEN RESULTS IN FULMINANT
INFECTION (70% CIRRHOSIS)
SURVIVORS RARELY DEVELOP
CHRONIC INFECTION (< 5%)
HDV INFECTION PATTERNS
• SUPERINFECTION
– RESULTS IN HDV SUPERINFECTION IN
AN HBsAg CARRIER (CHRONIC HBV)
– CAN OCCUR ANYTIME DURING
CHRONIC DISEASE
– USUALLY RESULTS IN RAPIDLY
PROGRESSIVE SUBACUTE OR
CHRONIC HEPATITIS
Nonenveloped Nonsegmented ssRNA
Viruses: Picornaviruses and Caliciviruses
• Picornaviruses
– Enterovirus – poliovirus, HAV
– Rhinovirus – rhinovirus
– Cardiovirus – infects heart and brain
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Poliovirus and Poliomyelitis
• naked capsid
• can survive stomach acids
when ingested
 Poliomyelitis (polio)
 acute enteroviral infection of the
spinal cord
 can cause neuromuscular
paralysis
• Worldwide vaccination
programs have reduced the
number of cases
– eradication is expected
Poliovirus
• Pretty tough virus: resistant to acid,
bile, & detergents, survives stomach
acids
• virus is ingested (food, water,
contaminated objects)
• most infections are mild
• grows in oropharynx & intestine, then
enters blood (viremia)
• if viremia persists, virus spreads to
spinal cord & brain
• invasion of motor neurons causes
flaccid paralysis
• decades later post-polio syndrome
(PPS) of muscle deterioration can
develop
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Diseases of the Enteroviruses
• Coxsackie A viruses
– Infection occurs via the
fecal-oral route
– Produce lesion and
fever
• Herpangina
• Hand-foot-and-mouth
disease
Human Rhinovirus (HRV)
• More than 110 serotypes (strains) associated with the common
cold
• Sensitive to acidic environments
– optimum temperature is 33oC
• Unique molecular surface makes development of a vaccine
unlikely
• Endemic with many strains circulating in the population at one
time
– acquired from contaminated hands and fomites
Hepatitis A virus particles found in fecal extracts by
immunoelectron microscopy. Both full and empty particles
are present. The virus is 27 to 29 nm in diameter. (X
125,000.)
Hepatitis A Transmission
Close personal contact
Household or sexual contact
Daycare centers
Fecal-oral contamination of food or water
Food handlers
Raw shellfish
Travel to endemic areas
Blood-borne (rare)
Injecting drug users
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Hepatitis A Vaccine Efficacy
Studies
Vaccine
Site/Age
Group
N
Vaccine
Efficacy
(95% CI)
HAVRIX
(SKB)
2 doses
360 EL.U.
Thailand
1-16 yrs
38,157
94%
(79%-99%)
VAQTA
(Merck)
1 dose
25 units
New York
2-16 yrs
1,037
100%
(85%-100%)
Epidemiology of Hepatitis E
Fecal-oral transmission (human to
human)
Contaminated water supplies in
tropical or subtropical
developing countries
Structural model of the
Hepatitis E virus
Mainly young adults
Can infect primates, swine, sheep,
rats
Swine may be reservoir of infection
in North America (attenuated
virus)
Maternal-infant transmission
occurs and is often fatal
Nonenveloped Segmented
dsRNA Viruses: Reoviruses
Unusual double-stranded RNA genome
Two best known:
• Rotavirus – oral-fecal transmission; primary
viral cause of mortality and morbidity resulting
from diarrhea in infants and children
– Treatment with rehydration and electrolyte
replacement
• Reovirus – cold-like upper respiratory infection,
enteritis
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RETROVIRUSES
HIV and AIDS
History of an infectious agent
In Los Angeles 1967-1978: only two cases of
Pneumocystis carinii pneumonia
• 1979 - 5 cases of Pneumocystis carinii
pneumonia
All Homosexual
Dot-like intracystic
bodies of Pneumocystis
carinii in lung
Cytologic preparation from a
bronchoalveolar lavage –
Giemsa stain
Pneumocystis
jiroveci
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HIV and AIDS
an infectious agent – Kaposi’s Sarcoma
Early 1981 MMWR: 5 cases of Kaposi’s
sarcoma
Hitherto: rare (immunocompromization)
Elderly - Non-aggressive
1981 - 26 cases of Kaposi’s sarcoma
• Young
• Male
• San Francisco and New York
• All Homosexuals
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HIV
HIV - Life History
HIV
chemokine
CD4
CD4
CCR5
CCR5
CD4
Mutant
CCR5
Chemokine receptors are macrophage
necessary co-receptors along with CD4 antigen
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Позавузлова лімфома
шиї
Саркома Капоші
Toxoplasma gondii
Candidosis
Anti-HIV Strategies
Highly
Active
AntiRetroviral
Therapy
HAART: Two nucleoside analog RT inhibitors and 1 protease inhibitor
Now also: Two nucleoside analog RT inhibitors and 1 non nucleoside
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