Transcript Negative (-) Single-Stranded RNA Viruses Samuel Aguazim M.D.

NEGATIVE (-) SINGLE-STRANDED
RNA VIRUSES
SAMUEL AGUAZIM M.D.
Lange Chapter 39
FAMILIES AND DISEASES
• Paramyxovirus – Parainfluenza, Respiratory
Syncytial Virus, measles (Rubeola), Mumps,
• Rhabdoviridae – Rabies Virus
• Filoviridae – Ebola and Marburg viruses
• Orthomyxoviridae - Influenza A and B Viruses
HIGH YIELD CONCEPTS
• Negative Sense RNA, abbreviated (-) RNA is the
homolog of mRNA
• All (-) RNA Viruses carry a virion-associated, RNAdependent RNA polymerase
• Naked (-) RNA (i.e., without the RNA dependent
RNA polymerase protein) is not infectious.
• All (-) RNA Viruses are helical and enveloped. No
(-) RNA viruses are naked or icosahedral.
• Three families of (-) SS RNA Viruses are
segmented: Orthomyxoviridae, Bunnaviridae,
and Arenaviridae
Myxo = affinity to mucin
Myxoviruses
Orthomyxo
viruses
Paramyxo
viruses
-Smaller
-Segmented RNA genome
-Liable to Ag variation
-Larger
-Single piece of RNA
- Not liable to Ag variation
Influenza viruses
- Parainfluenza
- Mumps virus
- Measles virus
- Respiratory
syncytial virus
INFLUENZA VIRUSES
• Replicate in mucus membranes
• Target tissue: upper & lower respiratory tract
• Cause influenza: acute respiratory disease that
may occur in epidemics or even pandemics
FAMILY
ORTHOMYXOVIRIDAEINFLUENZA A & B
• Segmented (8)
• Separate H (hemaglutinin) and (neuraminidase)
Glycoproteins
• Can lead to Guillain Barre (A or B) or Reye’s
syndrome (primarily B)
• Inactivated vaccine, H1N1 and H3N2
• Influenza A & B (also HIV) undergoes genetic
drift = slight changes in antigenicity due to
mutations (responsible for epidemics)
• Influenza A has a rare genetic shift
• Vaccine contains 2 A strains and one B strain:
Reformulated every year
Influenza: ORTHOMYXOVIRUSES
HA - hemagglutinin
NA - neuraminidase
helical nucleocapsid
(RNA plus NP protein)
lipid bilayer membrane
polymerase complex
M2 Protein
M1 protein
Haemagglutinin
 Binds to host cell
surface receptor
 The target of
neutralizing Abs
 Haemagglutinates RBCs
from various animal
species
Neuraminidase
 Cleaves neuraminic
acid to release virus
progeny from infected
cells
 Degrades the
protective layer of
mucin in the
respiratory tract
 Plays a min role in
immunity to influenza
Neuraminidase
Cleaves neuraminic acid to
release virus progeny from infected cells
Haemagglutinin
Binds to host cell surface receptor
INFLUENZA VIRUS: ANTIGEN DRIFT
ANTIGENIC DRIFT
•
•
•
•
•
•
Minor changes based on mutation in the genome RNA.
Drift variants occur every year
HA and NA accumulate mutations
immune response no longer protects fully
sporadic outbreaks, limited epidemics
Influenza B undergoes drift but not shift
ANTIGENIC SHIFT
• Major changes based on the reassortment of segments of the genome
RNA
• “new” HA or NA proteins
• Occur every 10 or 11 years
• pre-existing antibodies do not protect
• may get pandemics
WHERE DO “NEW” HA AND NA
COME FROM?
•13 types HA
• 9 types NA
•all circulate in
birds, pigs, avian
and human
hemaglutinin
Different
hemaglutinin
Influenza Virus
Antigenic Shift
• .
CLINICAL PICTURE
INCUBATION PERIOD: 1-4
DAYS
FEVER
Complications
•
•
pneumonia and respiratory failure
Reye,s Syndrome
Sore throat
cough
headache
50% of infected people don’t present any symptoms
But still contagious
This makes it difficult to stop the spread of the disease
INFLUENZA VIRUS IS LINKED TO REYE’S SYNDROME AND
GUILLIAN-BARRÉ SYNDROME
•
•
•
•
•
•
•
•
Reye’s syndrome
liver - fatty deposits
brain - edema
vomiting, lethargy, coma
risk factors
• youth
• certain viral infections (influenza, chicken pox)
• Aspirin
Guillian-Barré syndrome
Most common acute paralysis in the United State
Ab will form against myelin protein
Demyelination
1976/77 swine flu vaccine
• 35,000,000 doses
• 354 cases of GBS
• 28 GBS-associated deaths
• recent vaccines much lower risk
INFLUENZA A PANDEMICS
INFLUENZA VIRUS: VACCINE
• Killed influenza A and B viruses, typically two A strains and one B strain.
• The two A strains are recent H1Nl and H3N2 isolates.
• The vaccine is usually reformulated each year to contain the current
antigenic strains. Because the virus is killed, there is no replication in the
respiratory tract and, consequently, little secretory IgA appears on the
respiratory mucosa.
• The vaccine does induce IgG, which offers some protection.
• The vaccine is not a good immunogen, because little IgA is made and the
titer of IgG is relatively low.
• Protection lasts only 6 months.
• Yearly boosters are recommended and should be given shortly before the
flu season, e.g., in October.
• Boosters provide an opportunity to immunize against the latest antigenic
changes.
• The vaccine should be given to people older than 65 years of age and to
those with chronic diseases, particularly respiratory and cardiovascular
conditions. In 1994, the vaccination recommendations were expanded to
include all persons who want to reduce their risk of acquiring influenza
II- CHEMOPROPHYLAXIS
1)Amantadine & Rimantadipne:
 Prevent penetration & uncoating of the virus
 Treat & prevent influenza A only
 Given to high risk groups
2) Zanamavir & Oseltamivir (tamiflu)
 They are neuraminidase inhibitors, inhibiting the release of
virus from infected cells
 This limits the infection by reducing the spread of virus from
one cell to another
 For treatment not prevention
 Effective against influenza A &B
INFLUENZA VIRUS
• True influenza
• influenza virus A – worldwide epidemics
• influenza virus B – major outbreaks
• influenza virus C infections - much milder, does not cause
outbreaks
• recently some increase in morbidity and mortality - possible
factors?
• more elderly people
• more high risk neonates
• more immunosuppressed patients
INFLUENZA VIRUS
CDC WEBSITE
http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm
FAMILY PARAMYXOVIRUS
• Enveloped Helical nucleocapsid
• Negative sense ssRNA
• Fusion surface proteins
• Medical Important Virus
• Parainfluenza virus
• Respiratory Syncytial Virus (RSV)
• Mumps Virus
• Measles Virus (Rubeola)
CASE
• 2 year old female child, with fever for three
days, accompanied by cough, coryza and
conjunctivitis . Fever was high –grade, which
the mother managed with sponge baths
and Paracetamol. A reddish rash was later
noted on the child’s face, spreading to her
trunk and extremities. The child found it
difficult to sleep, since the rashes were itchy.
CASE
• On PE, the temperature was 40C, with harsh
breath sounds, no rales or wheezes.
• There was maculopapular rash, with some areas
being reddish in color, while others were
brownish.
CASE
•Maculopapular rash which extends
from
face to the extremities
CASE: CONJUNCTIVITIS
CASE:
KOPLIK
SPOTS
small (1 - 3mm), irregular, bright red
spots,
with bluish-white speck at center
opposite the
upper 2nd molars
CASE:
• IMPRESSION: Measles, uncomplicated
• TREATMENT : SUPPORTIVE
PATHOGENESIS & CLINICAL
PICTURE
• Replication initially in the upper & lower
respiratory tract
• Followed by LNs replication
• Viremia & growth in a variety of epithelial
tissue
• Incubation period: 1-2 wks
• In 2-3 days, no rash but fever, running nose,
cough & conjunctivitis
MEASLES VIRUS
(RUBEOLA)
• Symptoms generally the three C’s with
photophobia – Cough, coryza and conjunctivitis
• Koplik spots: grey-white spots with a red base on
the oral mucosa
• Rare Complication: subacute sclerosing
panencephalitis
• Erythematous maculopapular rash which starts on
the face and moves down. (rash results from the
action of cytotoxic T cells on infected cells in the
microcapillaries.
• Live attenuated vaccine (MMR)
• Pneumonia ( Warthin-Finkeldy cells)
pleomorphic
MEASLES
HA glycoprotein (1)
SPIKES
F glycoprotein (2)
SPIKES
helical nucleocapsid (RNA plus
NP protein)
lipid bilayer membrane
polymerase
complex
M protein
MEASLES RASH
KOPLIK SPOTS
1-Respiratory
symptoms
2-Koplick
spots
2-3 days
3-Maculopapular
rash
Persist 1-3 days
Disappear after the rash onset
Lasts for 3-7 day
4-Skin
exfoliation
Long life immunity due to IgG neutralizing Abs
The virus invades the body via blood vessels
reaches surface epithelium
first in the respiratory tract where
there are only 1-2 layers of epithelial cells
Then in mucosae (Koplik's spots)
and finally in the skin (rash).
Disorder
CLINICAL CONSEQUENCES
OF MEASLES VIRUS
symptoms
INFECTION
Measles
Characteristic maculopapular rash,
cough, conjunctivitis, coryza,
photophobia and koplik’s spot
Complication
Otitis media, croup,
bronchopneumonia and encephalitis
ATYPICAL MEASLES
RASH( most prominent in distal area)
possible vesicles, petechiae, purpura or
urticaria
Subacute sclerosing panencephalitis
Central nervous system
manifestation(e.g personality,
behaviour and memory changes,
myoclonic jerks, spasticity and
blindness
MUMPS VIRUS
• Causes epidemic parotitis ( non suppurative
inflammation of parotid)
saliva
• Mode of transmission:
• Via aerosols & fomites
• The virus is secreted in urine so urine is a
possible source of infection
PATHOGENESIS & CLINICAL
PICTURE
• Infects children 5-15years
• Replicates in the nasopharynx &regional LNs
• Incubation period: 2-25 d
Lasts 3-5 d
viremia
-Salivary
-Pancreas
-Testes
-ovaries
glands
meninges
Long life immunity due to IgG neutralizing Abs
pleomorphic
MUMPS
H/N glycoprotein
SPIKES
F glycoprotein
SPIKES
helical nucleocapsid (RNA plus
NP protein)
lipid bilayer membrane
polymerase
complex
M protein
MUMPS
• Live attenuated Vaccine
• Aseptic Meningitis
• Orchitis in postpubertal males (rarely causes sterility
except if bilateral)
• Parotitis
• Pancreatitis
***Memory Tool MOPP
HUMAN PARAINFLUENZA
VIRUSES(1,2,3,4)
• HPIVs are second to RSV as a common cause
of lower respiratory tract disease in young
children
• Similar to RSV, HPIVs can cause repeated
infections throughout life, usually upper
respiratory tract illness
• Can also cause severe lower respiratory tract
infections among immunocompromised
patients
• Each of the four HPIVs has different clinical &
epidemiologic features
• The most distinctive clinical feature of HPIV-1& HPIV-2 is
croup
• HPIV-3 is more associated with bronchiolitis & pneumonia
• HPIV-4 is infrequently detected, because it is less likely to
cause severe disease
Croup (laryngotracheobronchitis
difficulty in breathing, hoarseness and
a seal bark-like coughing
DIAGNOSIS OF CROUP
Chest radiograph depicting
subglottic narrowing, commonly
called the "steeple sign.
RESPIRATORY SYNCYTIAL
VIRUS
• Commonest cause of bronchitis & pneumonia among
infants< 1yr.
• Causes repeated infections throughout life, usually
associated with moderate- to severe cold –like
symptoms
• Severe lower respiratory tract disease may occur at any
age, especially elderly & those with compromised
cardiac, pulmonary or immune systems
RESPIRATORY SYNCYTIAL
VIRUSES
Pleomorphic: vary in shape
Syncytia = multinucleated giant
cells
F=fusion
F glycoprotein
SPIKES:
Ab against F, neutralizes
infectivity
helical nucleocapsid (RNA plus
NP protein)
lipid bilayer membrane
polymerase
complex
M protein
FAMILY RHABDOVIRIDAE
– RABIES VIRUS
• Bullet Shaped
• Negri Bodies – intracytoplasmic inclusion bodies
• Prevention: Inactivated vaccine; passive immunization
• Spread to humans by bites of Rabid dogs; contact with bats
• Eastern U.S. reservoirs: foxes & raccoons; western U.S.: skunks
TRANSMISSION
• BITE - USUAL ROUTE
• CORNEAL AND OTHER TRANSPLANTS
• MUCOSAL MEMBRANES, WOUND
• AEROSOL (RARE)
RABIES PATHOGENESIS
Virus is transmitted via bite
Agents are highly neurotropic
Enter peripheral nerves
Centripetal travel by
retrograde flow in axoplasm of
nerves to CNS
• Replicate in brain
• Centrifugal flow to innervated
organs, including the portal of
exit, the salivary glands
• Viral excretion in saliva
•
•
•
•
Note: No Viremia
Murray et al., Medical Microbiology
CLINICAL STAGES
• Incubation Period (range =
~<7 days to >6 years;
average is ~4-6 weeks)
• Prodromal Phase (Nonspecific signs)
• Acute Neurological Phase
• Coma
• Death (recovery from
rabies?)
SYMPTOMS
• Variable, often misdiagnosed
• Tingling, paresthesia at bite site
• Fever, headache, malaise, anorexia
• Nausea, vomiting, myalgia, hydrophobia
• Confusion, hallucinations, seizures, paralysis
• Coma, respiratory failure, death
CLINICAL PRESENTATION
• Furious Rabies
• Headache, fever, irritability, restlessness and
anxiety. muscle pains, salivation and vomiting.
• After a few days to a week the patient may
experience a stage of excitement and be
wracked with painful muscle spasms, triggered
sometimes by swallowing of saliva or water.
Hence they drool and learn to fear water (*
Hydrophobia).
• The patients are also excessively sensitive to air
blown on the face. The stage of excitement lasts
only a few days before the patient lapses into
coma and death.
• Once clinical disease manifests, there is a rapid,
relentless progression to invariable death,
despite all treatment.
CLINICAL PRESENTATION
• Dumb Rabies
Starts in the same way, but instead of
progressing into excitement, the subject
retreats steadily and quietly downhill, with
some paralysis, to death. Rabies diagnosis
may easily be missed.
POST-EXPOSURE
PROPHYLAXIS FOR RABIES
• After an animal bite, treatment consists of
- one dose of rabies immune globulin
- five doses of rabies vaccine over a 28-day
period.
•Rabies immune globulin and the first dose of
rabies vaccine are administered as soon as
possible after you've been exposed and have
reported the exposure to your doctor.
You're given the immune globulin by injection
around the site of the bite, and you receive
injections of the vaccine into your upper arm
muscle.
•
FAMILY BUNYAVIRIDAE
• California Encephalitis Virus
- Mosquito Borne
- young (<15 years) have more severe
cases
• Hantavirus (Sin Nombre Hantavirus
- Hanta virus pulmonary syndrome (cough,
myalgia, dyspnea, tachycardia, pulmonary edema
and effusion, and hypotension (mortality 50%)
- High endemic area: Four Corners region (UT,
AZ, NM, CO), but all of North America
ARENAVIRIDAE
• Lymphocytic Choriomengitis (LCM)
• Transmission: MICE & HAMSTER(US)
- Influenza like with meningeal signs
- Imported from South America
• Lassa Fever Virus
• Transmission: rodents, human to human( west Africa)
- West Africa
- Hemorrhagic fever characterized by multi-organ
involvement.
- 50% fatal
Thank you