???? Influenza

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???? Influenza

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• ?????? ?????

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???? ????? Flu

• Flu sometimes is confused with the common cold.
  However, the flu is caused by influenza virus,
  and is a much more severe disease than the common
  cold, which is caused by a different type of
  virus. Influenza is a more severe viral infection
  of the respiratory tract that shows the
  additional symptoms to those of the common cold
  (rapidly rising fever, chills, and body and
  muscle aches).
• Respiratory Syncytial Virus ??? ???? ????? ?????
  ???? ????? ????? ????.
• ??? ???? ?? ????? ?????? ????? ?"? ???? ?????????
  (Adenovirus 3) ???????? ????? ????????? ??? ??
  ????? flu" ????"? ?? ?? ??? ????? ??? ??????.
  ??? ???????? ?????? ?????? ????? ????? ???? ?????
  ??????.

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?????? ?????

• ?-400 ????? ????????, ????? ?????? ????? ?????
  ????? ??????.
• ????? ??????? Spanish Flu ??? ???????? ?????.
• 1918 - ???? ????? (influenza) ???? ????? ?? 20
  ?????? ??? ???, ??????? ????? ????? ? -I .
• ?????? ????? I ???? ???? ??????? ?-"???????".

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?????? ?????

• ??? ??????? ?????? ?? ????? ?????? ??????? ?????
  ?-50 ????? ???????? ?? ??? ?????? ?? ??.
• ????? ???? ?? ????? ???????? (1957-1958), ???
  ????? ?????? ?? 10 ????, ??? ???? ???????.
• ?????? ??? - Reye Syndrome - ??? ????? ??? ?????
  ?????? ?????? ???? ????. ????? ??????.

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INFLUENZA - the name

• Influenza is Italian for "influence", Latin
  influentia. It used to be thought that the
  disease was caused by a bad influence from the
  heavens.

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Flu ????

• ????? ?????? ?????? ??? ???? ????? ??? ??????.
  ??? ?? ??? ???? ??
• ???? ??????
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• "??????"

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CLINICAL FEATURES

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• Influenza is characterized by fever, myalgia,
  headache and pharyngitis. In addition there may
  be cough and in severe cases, prostration. There
  is usually not coryza (runny nose), which
  characterizes common cold infections.
• Infection may be very mild, even asymptomatic,
  moderate or very severe.

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Source

• The reservoir is acute infection in other human
  beings.

Spread

• Is rapid via aerial droplets and fomites with
  inhalation into the pharynx or lower respiratory
  tract.

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Incubation

• Is short 1-3 days. Rapid spread leads to
  epidemics

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Complications

• Tend to occur in the young, elderly, and persons
  with chronic cardio-pulmonary diseases.
• Consist of
• 1. Pneumonia caused by influenza itself
• 2. Pneumonia caused by bacteria (not influenza
  virus itself)
• - Haemophilus influenzae ,
• - Staphylococcus aureus ,
• - Streptococcus pneumoniae .
• 3. Other viral superinfection, eg. Adenovirus.
• Overall death rates increase in times of
  influenza epidemics.

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Types of influenza virus

• There are three types of influenza
• Influenza C - Common but seldom causes disease
  symptoms
• Influenza B - Often causes sporadic outbreaks of
  illness, especially in residential communities
  like nursing homes.
• Influenza A - Responsible for regular outbreaks,
  including the one of 1918. Influenza A viruses
  also infect domestic animals (pigs, horses,
  chickens, ducks) and some wild birds.

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Structure of influenza A virus

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• ????? (Spikes)
• 8 ?????? ?? ??"? ??-????? (?????)
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In the lipid bilayer there are two integral
membrane proteins Hemagglutinin H and
neuraminidase - N
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Influenza Viruses. Morphology

• Influenza virus particles are highly pleomorphic,
  mostly spherical/ovoid, many forms occur.
• The outer surface of the particle consists of a
  lipid envelope from which project prominent
  glycoprotein spikes.
• The inner side of the envelope is lined by the
  matrix protein.
• The genome segments are packaged into the core.

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Genomic organization of influenza A virus

• The (-) strand RNA genome comprises 8 segments,
  each encodes at least one protein
• 1) 3 distinct hemagglutinins H1, H2, and H3
• 2) 2 different neuraminidases N1 and N2
• 3) nucleoprotein
• 4) matrix proteins
• 5) NS (nonstructural proteins, that are not
  incorporated into viral particles) gene encodes
  two different non-structural proteins
• 6)-8) subunits of RNA polymerase

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Subtypes of influenza A

• The hemagglutinin of the 1918 flu virus was H1,
  its neuraminidase was N1, so it is designated as
  an H1N1 "subtype".
• Flu pandemics occur when the virus acquires a new
  hemagglutinin and/or neuraminidase.

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Taxonomy Family Orthomyxoviridae

• 1.Genus Influenzavirus A
• Type species influenza A virus
• 2.Genus Influenzavirus B
• Type species influenza B virus
• 3.Genus Influenzavirus C
• Type species influenza C virus
• 4.Genus Thogotovirus
• Type species Thogoto virus

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OrthomyxovirusesInfluenza A Viruses

• Infect a wide variety of mammals, including man,
  horses, pigs, ferrets and birds.
• Pigs and birds are believed to be particularly
  important reservoirs, generating pools of
  genetically/antigenically diverse viruses which
  get transferred back to the human population via
  reassortment (close contact between pigs and man
  in the far east Ducks - migration!).
• The main human pathogen, associated with
  epidemics and pandemics.

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OrthomyxovirusesInfluenza B Viruses.

• Infect much man and birds.
• Cause human disease but generally not as severe
  as A types.
• Believed to be epidemiologically important -
  reassortment with type A leads to epidemics.

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????? ?????Influenzavirus A

• Virions enveloped
• About 500 spikes
• Nucleocapsid enclosed within lipoprotein membrane
• Virions contain 8 segments of linear
  negative-sense single stranded RNA
• Total genome length is 13588 nt
• The largest segment 2341 nt

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????? ?????Influenzavirus B

• Virions enveloped
• About 500 spikes
• Nucleocapsid enclosed within lipoprotein membrane
• Virions contain 8 segments of linear
  negative-sense single stranded RNA
• Total genome length is 13588 nt
• The largest segment 2341 nt

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????? ?????Influenzavirus C

• Virions enveloped
• Many spikes
• Nucleocapsid enclosed within lipoprotein membrane
• Virions contain 7 segments of linear
  negative-sense single stranded RNA
• Total genome length is 12900 nt
• The largest segment 2300-2500 nt

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OrthomyxovirusesInfluenza C Viruses.

• Influenza C viruses infect man alone, but do not
  cause disease (?).
• They are genetically and morphologically distinct
  from A and B types - little studied.

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????? ??????? - Single-cell reproductive cycle

• 1. Attachment to the epithalial cells of the host
  through hemagglutinin.
• 2. Endocytosis
• 3. Uncoating -gt This exposes the contents of the
  virus to the cytosol.
• 4.The RNA enter the nucleus of the cell where
  fresh copies are made.
• 5. These copies return to the cytosol where some
  serve as mRNA molecules to be translated into the
  proteins of fresh virus particles.
• 6. Fresh virus buds off from the plasma membrane
  of the cell (aided by the neuraminidase) thus
  spreading the infection to new cells.

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????? ??????? - Single-cell reproductive cycle

• 3) Replication (mRNA)
• 5) Transport
• 6) Splicing
• 7,8,9) Translation
• 10) Import
• 11,12,13) Catalysis of synthesis

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Assembly ??? ??????

• 1. Packaging
• 2. Little is known
• 3. NS2 binding and export of the nucleocapsid to
  the cytoplasm
• 4. M1 directs the nucleocapsid to the membrane
• 5.Viral proteins reach the site
• 6. Budding
• 7. Release

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Life-cycle

• New viral proteins are translated from
  transcribed messenger RNA (mRNA).
• New viral RNA is encased in the capsid protein,
  and together with new matrix protein is then
  transported to sites at the cell surface where
  envelope haemagglutinin and neuraminadase
  components have been incorporated into the cell
  membrane.
• Progeny virions are formed and released by
  budding.
• The cell does not die (at least not initially).

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Influenza Viruses. Replication
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Influenza Viruses. Replication

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• After binding, the particle is engulfed by
  endocytosis via coated pits (?????) into
  endocytotic vesicles and finally endosomes.
• Specific nuclear targeting sequences result in
  translocation of the nucleocapsid (?????? ??????)
  into the nucleus.

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????? ??????? - A
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????? ??????? - Single-cell reproductive cycle

• 1. Endocytosis
• 2. Release nucleocapsids
• 3. Transport into the nucleus
• 4. Copying by RNA polymerase into viral mRNA
• 5. Transport to the cytoplasm
• 6. Splicing

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????? ??????? - Single-cell reproductive cycle

• 6. Splicing of NS2 and M2
• 7. Translation of Ha, Na, M2
• 8,9. Translation
• 10. Import into the nucleus of PA, PB1, PB2, and
  NP proteins
• 11. Synthesis of full-length () RNAs

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Assembly

• 1. Packaging
• 2. Little is known
• 3. NS2 binding and export of the nucleocapsid to
  the cytoplasm
• 4. M1 directs the nucleocapsid to the membrane
• 5.Viral proteins reach the site
• 6. Budding
• 7. Release

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Life-cycle

• New viral proteins are translated from
  transcribed messenger RNA (mRNA).
• New viral RNA is encased in the capsid protein,
  and together with new matrix protein is then
  transported to sites at the cell surface where
  envelope haemagglutinin and neuraminadase
  components have been incorporated into the cell
  membrane.
• Progeny virions are formed and released by
  budding.
• The cell does not die (at least not initially).

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Influenza Viruses. Replication

• The virus attaches to the outside of the host
  cell and its RNA enters into the cell.
• The viral genes are transcribed and translated by
  the cell's enzymes and ribosomes.
• In this way, the virus takes over the cell's
  productivity.

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Influenza Viruses. Replication

• Now, instead of producing only new cellular
  material, the cell produces hundreds of new virus
  particles.
• The new virus particles are eventually released
  from the cell and drift off, and some may land on
  a host cell of their own to pirate.

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Influenza Viruses. Replication

• Virus particles are gradually released from the
  surface of the cell over a period of several
  hours.
• The cell does not lyse, but eventually dies (due
  to disturbance of normal cellular macromolecular
  synthesis?).

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Influenza. Pathogenesis

• Spread is by aerosols.
• The influenza virus invades cells of the
  respiratory passages. Primary infection involves
  the ciliated epithelial cells in the nose, throat
  and intestines of birds.
• Necrosis of these cells results in the usual
  symptoms of the acute respiratory infection
  (fever, chills, muscular aching, headache,
  prostration, anorexia).

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Influenza. Pathogenesis

• Normally self-limited infection usually lasts 3-7
  days (???? ?????).
• It usually does not kill the patient (the 1918
  pandemic was an exception some victims died
  within hours) but does expose the lungs to
  infection by various bacterial invaders that can
  be lethal. Damage to respiratory epithelial cells
  predisposes to secondary bacterial infections
  which accounts for most deaths.

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Virus reassortment

• H and N are encoded by separate RNA molecules.
• If an animal is simultaneously infected by two
  different subtypes, these genes can be
  reassorted.

• For example pigs simultaneously infected with
  swine flu virus (H1N1) and the Hong Kong virus
  (H3N2) H3 and N1 are reassorted in a pig and a
  new H3N1 virus appears.
• Reassortment can also occur in humans with dual
  infections.

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Virus reassortment
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Antigenic shifts
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• A vaccine formulated for one year may be
  ineffective in the following year, since the
  influenza virus changes rapidly over time and
  different strains become dominant.

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• Some vaccines incorporate inactivated virus
  particles others use the purified hemagglutinin.
  Both types incorporate antigens from the three
  major strains in circulation, (the trivalent flu
  vaccine) currently
• an A strain of the H1N1 subtype
• an A strain of the H3N2 subtype and
• a B strain.
• Antiviral drugs can be used to treat influenza

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What is avian influenza?

• Avian influenza, or bird flu, is a contagious
  disease of animals caused by viruses that
  normally infect only birds and, less commonly,
  pigs. Avian influenza viruses are highly
  species-specific, but have, on rare occasions,
  crossed the species barrier to infect humans.
• In domestic poultry, infection with avian
  influenza viruses causes two main forms of
  disease, distinguished by low and high extremes
  of virulence. The so-called low pathogenic form
  commonly causes only mild symptoms (ruffled
  feathers, a drop in egg production) and may
  easily go undetected. The highly pathogenic form
  is far more dramatic. It spreads very rapidly
  through poultry flocks, causes disease affecting
  multiple internal organs, and has a mortality
  that can approach 100, often within 48 hours.

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Which viruses cause highly pathogenic disease?

• Influenza A viruses have 16 H-subtypes and 9
  N-subtypes. Only viruses of the H5 and
  H7 subtypes are known to cause the highly
  pathogenic form of the disease. However, not all
  viruses of the H5 and H7 subtypes are highly
  pathogenic and not all will cause severe disease
  in poultry.
• On present understanding, H5 and H7 viruses are
  introduced to poultry flocks in their low
  pathogenic form. When allowed to circulate in
  poultry populations, the viruses can mutate,
  usually within a few months, into the highly
  pathogenic form. This is why the presence of an
  H5 or H7 virus in poultry is always cause for
  concern, even when the initial signs of infection
  are mild.

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What is special about the current outbreaks in
poultry?

• The current outbreaks of highly pathogenic avian
  influenza, which began in South-east Asia in
  mid-2003, are the largest and most severe on
  record.
• Never before in the history of this disease have
  so many countries been simultaneously affected,
  resulting in the loss of so many birds.

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What is special about the current outbreaks in
poultry?

• The causative agent, the H5N1 virus, has proved
  to be especially tenacious.
• Despite the death or destruction of an estimated
  150 million birds, the virus is now considered
  endemic in many parts of Indonesia and Vietnam
  and in some parts of Cambodia, China, Thailand,
  and possibly also the Lao Peoples Democratic
  Republic.
• Control of the disease in poultry is expected to
  take several years.

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What are the implications for human health?

• The widespread persistence of H5N1 in poultry
  populations poses two main risks for human
  health.
• The first is the risk of direct infection when
  the virus passes from poultry to humans,
  resulting in very severe disease.
• Of the few avian influenza viruses that have
  crossed the species barrier to infect humans,
  H5N1 has caused the largest number of cases of
  severe disease and death in humans.

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What are the implications for human health?

• Unlike normal seasonal influenza, where infection
  causes only mild respiratory symptoms in most
  people, the disease caused by H5N1 follows an
  unusually aggressive clinical course, with rapid
  deterioration and high fatality.
• Primary viral pneumonia and multi-organ failure
  are common. In the present outbreak, more than
  half of those infected with the virus have died.
  Most cases have occurred in previously healthy
  children and young adults.

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What are the implications for human health?

• A second risk, of even greater concern, is that
  the virus if given enough opportunities will
  change into a form that is highly infectious for
  humans and spreads easily from person to person.
• Such a change could mark the start of a global
  outbreak (a pandemic).

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How do people become infected?

• Direct contact with infected poultry, or surfaces
  and objects contaminated by their feces, is
  presently considered the main route of human
  infection. To date, most human cases have
  occurred in rural or periurban areas where many
  households keep small poultry flocks, which often
  roam freely, sometimes entering homes or sharing
  outdoor areas where children play.
• As infected birds shed large quantities of virus
  in their feces, opportunities for exposure to
  infected droppings or to environments
  contaminated by the virus are abundant under such
  conditions.

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How do people become infected?

• Moreover, because many households in Asia depend
  on poultry for income and food, many families
  sell or slaughter and consume birds when signs of
  illness appear in a flock, and this practice has
  proved difficult to change.
• Exposure is considered most likely during
  slaughter, defeathering, butchering, and
  preparation of poultry for cooking.

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What about the pandemic risk?

• A pandemic can start when three conditions have
  been met a new influenza virus subtype emerges
  it infects humans, causing serious illness and
  it spreads easily and sustainably among humans.
  The H5N1 virus amply meets the first two
  conditions it is a new virus for humans (H5N1
  viruses have never circulated widely among
  people), and it has infected more than 100
  humans, killing over half of them. No one will
  have immunity should an H5N1-like pandemic virus
  emerge.

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What about the pandemic risk?

• All prerequisites for the start of a pandemic
  have therefore been met save one the
  establishment of efficient and sustained
  human-to-human transmission of the virus. The
  risk that the H5N1 virus will acquire this
  ability will persist as long as opportunities for
  human infections occur. These opportunities, in
  turn, will persist as long as the virus continues
  to circulate in birds, and this situation could
  endure for some years to come.

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H5N1 Candidate Vaccines??????? ?????? ??? H5N1

• A universal influenza vaccine could provide
  protection against all types of influenza and
  would eliminate the need to develop individual
  vaccines to specific H and N virus types.
• British company Acambis announced in early August
  2005 that it has had successful results in animal
  testing.
• The vaccine focuses on the M2 viral protein,
  which does not change, rather than the surface
  hemagglutinin and neuraminidase proteins targeted
  by traditional flu vaccines.
• Still, such a vaccine is years away from full
  testing, approval, and use.