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Orthomyxoviruses (Influenza virus)


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Title: 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.

  • Major cause of respiratory disease. Influenza
    (flu) can cause mild to severe illness, and has
    been responsible for millions of deaths
  • ss negative-sense RNA. The antisense RNA genome
    occurs in eight separate segments containing 10
  • 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
  • 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

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
  • Functions at the end of viral replication cycle.
    It is a sialidase that removes sialic acid from
  • Facilitates release of virus particles from
    infected cell surfaces during the budding
    process. And prevent self-aggregation 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 ReplicationExpert Reviews in
Molecular Medicine 2001 Cambridge University Press
  • (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
  • 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

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.
  • Reyes Syndrome an acute encephalopathy of
    children and adolescents (2-16yrs)

  • 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.

  • 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.

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Prevention Control by Vaccines
  • A) Inactivated Viral Vaccines
  • Parenteral useusually contain 1 or 2 type A and
    a type B viruses, isolated from previous winters
  • 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.
    WVcontains intact, inactivated virus
    SVpurified virus disrupted with detergents SAg
    contains purified HA and NA glycoproteins.
  • Sometimes called flu shot or flu jab.

Prevention Control by Vaccines
  • 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).

  • 25 Muharram 1428H
  • 13 Feb 2007
  • SBM 2044

  • 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
  • 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
  • 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
  • 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 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
  • 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
  • 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. 20-50 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 lt 6 mth.

  • Mumps virus is isolated from saliva, CSF, urine.
  • Serology detect mumps-specific 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).

  • No specific therapy.
  • Immunisation with attenuated live mumps virus
    vaccine to reducing mumps-associated morbidity
    and mortality.
  • Isolation of infected subjects to prevent
  • Mumps vaccine available in MMR (mumps, measles
    and rubella). Produce Abs to each viruses in 95

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)
  • 1 viraemia
  • Reticuloendothelial
  • 2 viraemia

  • epithelial surface
  • Skin resp T conjunctiva

Aids dissemination throughout body - seen as
multinucleated giant cells
  • 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 Kopliks 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
  • 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.

  • 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
  • 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
  • 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 ?
  • 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
  • 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
  • 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
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