Transcript Orthomyxoviruses (Influenza virus)

Orthomyxoviruses
(Influenza virus)
25 Muharram 1428H
13 Feb 2007
SBM 2044
► In
1918 children would skip rope to the
rhyme*:
I had a little bird,
Its name was Enza.
I opened the window,
And in-flu-enza.
*
Taken from Crawford, Richard, "The Spanish Flu," Stranger Than
Fiction: Vignettes of San Diego History San Diego Historical Society,
1995
The influenza pandemic of 1918-1919 killed
more people than the World War I (WWI),
at somewhere between 50 and 100 million
people. This was caused by the deadly
strain subtype H1N1 influenza type A virus.
It has been cited as the most devastating
epidemic in recorded world history. More
people died of influenza in a single year
than in four-years of the Black Death
Bubonic Plague from 1347 to 1351.
Orthomyxoviruses
► Major
cause of respiratory disease. Influenza (flu)
can cause mild to severe illness, and has been
responsible for millions of deaths worldwide.
► ss negative-sense RNA. The antisense RNA
genome occurs in eight separate segments
containing 10 genes.
► The envelope contains viral haemagglutinin (HA)
and neuraminidase (NA) proteins.
► Genetic reassortment of Influenzavirus is common.
The segmented viral genome allows a mixture of
genome segments from two strains, when a single
cell is infected by 2 different strains.
Influenza virus
Classification
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Antigenic differences exhibited by two of the internal
structural proteins: nucleocapsid (NP) and matrix (M)
proteins, are used to divide influenza viruses into types
AC. NP antigens are stable and exhibit no serologic cross
reactivity.
Surface glycoproteins: HA and NA, are used to subtype the
viruses. These two antigens are variable. These Ags are
responsible for immunity to infection.
So far, 15 subtypes for HA (H1-H15); and
9 subtypes for NA (N1-N9) have been recovered from
birds, animals and humans.
In humans, there are 4 HA (H1-3,H5) and 2 NA (N1-2).
Function of HA
► Haemagglutinin
= agglutinate erythrocytes
under certain conditions.
► HA binds virus particles to susceptible cells,
and is the major Ag against neutralising
Abs.
Function of NA
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Functions at the end of viral replication cycle. It is a
sialidase that removes sialic acid from glycoconjugates.
Facilitates release of virus particles from infected cell
surfaces during the budding process. And prevent selfaggregation of virions by removing sialic acid residues from
viral glycoproteins. Also may help the virus to slide
through the mucin layer in resp T to reach the target
epithelial cells.
Influenza virus Replication
Expert Reviews in Molecular Medicine 2001 Cambridge University Press
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(a) The virus binds to cell-surface sialic acid receptors on the
surface of the host cell and (b) is internalised into endosomes, by
receptor-mediated encytosis. (c) Fusion btw viral envelope and cell
membrane, and uncoating events, (d) Low pH is required by the
virus-mediated membrane fusion to release of the viral genome
(RNPs) into the cytoplasm. The vRNPs are then imported into the
nucleus for (e) replication. (f) mRNAs are produced from viral
nucleocapsids. Positive-sense viral messenger RNAs (mRNAs) are
exported out of the nucleus into the cytoplasm for (g) protein
synthesis. Cellular functions are more involved. Protein synthesis
requires cellular transcripts and RNA polymerase II, which
explains why influenza virus is inhibited by drugs that
block cellular transcription. (h) Some of the proteins are
imported into the nucleus to assist in viral RNA replication and (i)
vRNP assembly, which also occur in the nucleus. (j) Late in
infection, the vRNPs form and leave the nucleus, and (k) progeny
viruses assemble and (l) bud from the plasma membrane.
The sites of action of anti-viral drugs are shown in red, italic text.
Abbreviations used: cRNA (+), positive-sense complementary RNA;
HA, haemagglutinin; M1, matrix protein; M2, tetrameric ion
channel; mRNA (+), positive-sense messenger RNA; NA,
neuraminidase; NP, nucleoprotein; NS1, a non-structural protein,
NS2, a viral protein; pols, polymerases; vRNA (-), negative-sense
genomic RNA
Pathogenesis & Pathology
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Spreads from person to person by airborne droplets, or
contaminated hands and surfaces.
Viral NA lowers the viscosity of the mucous film in the resp
T, exposing the cellular surface receptors and promoting
the spread of virus-containing fluid to lower resp T. Within
short time, many resp cells are infected and eventually
killed.
Interferon is effective against influenza virus and attributes
to host recovery.
Influenza infections cause cellular destruction and
desquamation of superficial mucosa of the respiratory tract
but do not affect the basal layer of epithelium. Viral
damage in the epith lowers its resistance to secondary
bacterial invaders esp staphylococci, streptococci and
Haemophilus influenzae.
Antigenic Drift & Shift
► Antigenic
variants confer selective advantage over
the parental virus in the presence of Ab against
the original strain.
► The 2 surface Ags undergo antigenic variation
independent of each other.
► Antigenic drift = Minor changes, a gradual change
in antigenicity due to point mutations that affect
major antigenic sites on the glycoprotein.
► Antigenic shift = Major changes, an abrupt change
due to genetic reassortment with an unrelated
strain, which results in the appearance of a new
subtype.
Clinical findings
► Uncomplicated
Influenza : Abrupt symptoms
include chills, headache, dry cough, muscular
aches. These may be induced by influenza A or B.
In contrast, influenza C causes a common cold
illness, Coryza.
► Pneumonia : complications occur only in the
elderly and debilitated. Influenza infection
enhances the susceptibility of patients to bacterial
superinfection, due to loss of ciliary clearance,
dysfunction of phagocytic cells.
► Reye’s Syndrome : an acute encephalopathy of
children and adolescents (2-16yrs)
Immunity
Is long-lived and subtype specific.
Abs to HA and NA are important. Resistance to initiation
of infection is related to Ab vs. HA, whereas severity of
disease and ability to transmit virus to contacts are
associated with Abs vs. NA.
► Local secretory IgA Abs is probably important in
preventing infection. Serum Abs are also protective and
persist for years. Abs modify the course of illness –
person with low titres of Abs may experience mild form
of illness.
► Cell-mediated immune response is probably important
for clearance of an infection. Cytotoxic T lymphocyte
response is cross-reactive ie. able to lyse cells infected
by any subtype of virus, and is directed against both
internal proteins (NP, M) and the surface glycoproteins.
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Epidemiology
► Periodic
outbreaks appear because of antigenic
changes in one or both surface glycoproteins of
the virus.
► Only influenza A viruses circulate in animals and
avians. Antigenic shift ?
► The recent strain in avian influenza A virus (H5N1)
in 1997, reported in Hong Kong. The source was
domestic poultry. At present, there is no vaccine
against this strain.
Prevention & Control by Vaccines
A) Inactivated Viral Vaccines:
► Parenteral use;usually contain 1 or 2 type A and a type B
viruses, isolated from previous winter’s outbreaks.
► Strains are grown in embryonated eggs and the virus is
harvested from egg allantoic fluid.
► Vaccines are either whole virus (WV), subvirion (SV), or
surface Ag (SAg) preparations. WV=contains intact,
inactivated virus; SV=purified virus disrupted with
detergents; SAg contains purified HA and NA glycoproteins.
► Sometimes called “flu shot” or “flu jab”.
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Prevention & Control by Vaccines
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B) Live Attenuated Influenza Vaccine
Contains live but attenuated (weakened) vaccine. It is
sprayed into nostril.
For both types of vaccines, it will take up to 2 weeks to
develop protection after vaccination.
The synthetic drugs amantadine and rimantadine
hydrochloride effectively prevent infection and illness
caused by type A, but not by type B, viruses. The drugs
interfere with virus uncoating and transport by blocking the
transmembrane M2 ion channel (see fig of replication).
Paramyxoviruses
25 Muharram 1428H
13 Feb 2007
SBM 2044
Paramyxoviruses
► The
World Health Organisation (WHO) estimates
that acute respiratory infections and pneumonia
are responsible every year worlwide for the deaths
of 4 million children under 5 years of age.
► Paramyxoviruses are the major respiratory
pathogens in this age group.
► Reinfections are common throughout childhood.
► All members of the Paramyxoviridae family initiate
infection via the resp T.
► Transmission is by person-to-person contact or by
large-droplet aerosols.
General Structure
► Enveloped.
Viral
genome is linear,
negative sense ss RNA.
Non-segmented
genome, hence all
members are
antigenically stable.
► Haemagglutinin
glycoprotein HN
proteins are important
for viral attachment.
Pathogenesis of Parainfluenza
Infections
► Parainfluenza
virus replication in
immunocompromised appears to be limited to
respiratory epithelia. Viraemia is rare. The result is
“common cold” syndrome.
► Infection may spread to larynx and upper trachea,
resulting in croup. Croup is characterised by resp
obstruction due to swelling of larynx and related
structures.
► Viral shedding is about 1 week after onset of
illness. Some immunocompromised children
experience persistent shedding.
Clinical findings & Lab diagnosis
► Primary
infections in children usually result in
rhinitis, pharyngitis, often with fever.
► Severe illness associated with Parainfluenza Type 3
may occur in infants.
► Common complication is otitis media.
► Lab: Ag detection – immunofluorescence test;
isolation of virus-containing specimens; and
serological by detecting specific IgM Ab.
► Parainfluenza viruses are troublesome in hospitals.
Contact isolation is necessary to prevent
outbreaks.
► Antiviral ribavirin is used to treat
immunocompromised with lower resp T disease.
Respiratory Syncytial Virus
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Most important cause of lower resp T illness in infants and
young children.
Replication occurs initially in epithelial cells of the
nasopharynx. Virus may spread into the lower resp T and
cause bronchiolitis and pneumonia.
The incubation period between exposure and onset of
illness is 3-5 days.
Viral shedding may persist 1-3 weeks in children; and 1-2
days only in adults.
RSV initially replicates in epithelial cells of nasopharynx,
which then migrates to the lower resp T and causes
bronchiolitis and pneumonia. The virus spreads both
extracellularly and by fusion of cells to form syncytia.
Treatment
► Treatment
on supportive care (eg. removal of
secretions, administration of O2)
► A promising means of protection is the
administration of RSV-enriched polyclonal
immunoglobulin (RSVIG) with monthly high-dose
infusion. The maintenance of high-titer RSV
neutralizing antibodies seems to significantly
decrease the incidence and severity of respiratory
syncytial virus illness in children at high risk.
► Ribavirin – in the US.
► As yet, there is no safe and effective vaccine
against RSV.
Mumps Virus
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Is an acute contagious disease
characterised by non-suppurative
enlargement of one or both
salivary glands.
Mostly causes mild childhood
disease, but in adults,
complications inc meningitis and
orchitis are common.
More than 1/3 of mumps infections
are asymptomatic, but equally capable of transmitting
the virus.
Humans are the only natural hosts.
Pathogenesis & Pathology
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Primary replication occurs in nasal and upper resp T epithelial
cells  viraemia  salivary G & other organs (NB. Parotid G
is not compulsory)
Incubation period may range from 2-4 wks.
Virus shed in saliva from about 2 days before to 9 days after
the onset of salivary G swelling.
It is difficult to control transmission since mumps is
asymptomatic and has a variable incubation periods.
Virus frequently infects kidneys, detectable in urine. CNS is
commonly infected and may be involved in the absence of
parotitis.
Testes and ovaries may be affected, esp after puberty. 2050% of males infected with mumps virus develop orchitis,
and lack elasticity of the tunica albuginea which prevents
testis to swell. This results in pressure necrosis, but rarely
results in sterility. 5 % of women develops mumps
oophoritis.
Immunity vs. Mumps Virus
► Immunity
is permanent after a single
infection.
► Only one antigenic type of mumps virus.
► Abs develop against surface glycoproteins
and internal nucleocapsid protein.
► Interferon induced early in mumps infection.
IgA secreted in nasopharynx.
► Passive immunity from motheroffspring.
Hence, rare mumps in infants < 6 mth.
Diagnosis
► Mumps
virus is isolated
from saliva, CSF, urine.
► Serology: detect mumpsspecific IgM or IgG.
► Mumps primarily is an
infection of children 5-9 yrs
is the highest incidence.
► Transmission by close
contact eg. Crowded areas
(army camps).
Treatment
► No
specific therapy.
► Immunisation with attenuated live mumps
virus vaccine to reducing mumps-associated
morbidity and mortality.
► Isolation of infected subjects to prevent
outbreak.
► Mumps vaccine available in MMR (mumps,
measles and rubella). Produce Abs to each
viruses in ~95% vaccinees.
Histological
diagnosis:
Haemadsorption
by Mumps virus
Large syncytia
by Respiratory
Syncytial virus
Measles (Rubeola) Virus
► Measles
is an acute, highly infectious
disease characterised by fever, resp
symptoms and maculopapular rash.
► Complications are common.
► Although there is a vaccine, incidence is
low, but still a leading cause of death in
young children in developing countries.
► Humans are the only host. Other animals
can be experimentally infected.
Pathogenesis & Pathology
Virus enters resp T (and multiply locally)
Lymphoid tissues (more multiplication)
Aids dissemination throughout
body - seen as
multinucleated giant cells
1° viraemia
Reticuloendothelial
2° viraemia
Skin
resp T
epithelial surface
conjunctiva
Pathogenesis
► Rash
appears at about day 14, just as circulating
Ab is detectable, viraemia disappears and fever
falls. Rash develops as a result of interaction of
immune T cells with virus-infected cells in the
small blood vessels and lasts about 1 week. (Thus,
patients with defective cell-mediated immunity will have no rash)
► Brain/CNS
infection is common. Complication 
subacute sclerosing panencephalitis that develops
years after infection, caused by viruses remaining
in the body.
► Viral replication is defective owing to the lack of
production of one or more viral gene products,
often matrix protein.
Clinical Findings
Fever, sneezing, coughing, running nose and redness of
eyes; Koplik’s spots (small bluish-white ulcerations on the
buccal mucosa opposite lower molars) and lymphopenia.
► Rash starts on head, spreads to the chest, trunk, lower
limbs.
► Pneumonia – most common life-threatening complications
of measles, by 2° bacterial infections.
► More serious complications  acute encephalitis
► Subacute sclerosing panencephalitis occur insidiously 5-15
yrs after case of measles, characterised by progressive
mental deterioration, involuntary movements, muscular
rigidity and coma.
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Immunity
► There
is only one antigenic type, hence
infection confers lifelong immunity.
► Patients with Ig-defective recover well,
whereas cellular immune-deficiency do
poorly.
► Abs to nucleoprotein is the most useful –
the most abundant viral protein in cells.
Epidemiology and Treatment
► Transmission
is predominantly via resp route.
Haematogenous transplacental transmission
during pregnancy.
► Continuous supply of susceptible individuals is
required for the virus to persist in a community.
► Measles is endemic worldwide. Epidemics recur
regularly every 2-3 years.
► Rx: live attenuated measles virus vaccine
(monovalent or combination with rubella – MMR).
► Vaccinees may experience mild clinical reactions,
but no virus excretion and no transmission.
Nipah Virus & Hendra Virus
► Zoonotic paramyxoviruses.
► 1998-99: severe encephalitis
in Malaysia by Nipah
virus. High mortality rate up to 70%. Infection
caused by direct viral transmission from pigs to
humans.
► Hendra virus is an equine virus.
► Fruit bats (flying foxes) are natural hosts for both
Nipah and Hendra viruses.
► Ecologic changes inc land use and animal
husbandry practices are probably the reason for
the emergence of these two infectious diseases.
Rubella/German Measles
► Is
an acute febrile illness characterised by a
rash and lymphadenopathy that affects
children and young adults. A self-limiting
illness.
► It is the mildest of common viral exanthems
but infection during early pregnancy may
results in congenital malformations and
mental retardation.
► Rubella virus is a member of Togaviridae.
Postnatal Rubella
► Neonatal,
children and adults may be infected
whereby infections starts in upper resp T, and
multiplication in cervical lymph nodes  viraemia.
► Fever, malaise and a morbiliform rash. Rash starts
on face, extends over trunk and extremities. But
rarely lasts more than 3 days.
► Lab diagnosis is unreliable because similar
symptoms are seen with other viruses.
Congenital Rubella
Occurs when maternal viraemia placenta and foetus
► In infected foetus, growth rate is reduced, results in
deranged/hypoplastic organ development. The earlier in
the pregnancy infection occurs, the greater the damage to
the foetus.
► Newborn will have cardiac abnormalities, deafness, rash,
hepatosplenomegaly and jaundice. Rubella panencephalitis
(rare) in second decade of life.
► Immunity: IgG = maternal rubella Ab which lost after
6mths; IgM = diagnostic of congenital rubella, since IgM
does not cross placenta, so its presence concurs the IgM
synthesis by infants in utero.
► Rx: No specific treatment. Best to prevent the disease.
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