Transcript influenza virus gp5 pcl ii

INTRODUCTION
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Influenza viruses are the only members of the
orthomyxovirus family.
The orthomyxoviruses differ from the paramyxoviruses
primarily in that the former have a segmented RNA
genome (usually eight pieces), whereas the RNA genome of
the latter consists of a single piece.
The term "myxo" refers to the observation that these
viruses interact with mucins (glycoproteins on the surface
of cells).
DISCOVERY OF INFLUENZA VIRUS
First
isolated
from a pig in
1931 (swine
flu)
Isolated from
human in
1933
EPIDEMIOLOGY:SEASONAL VARIATIONS
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Seasonal risk
areas for
influenza:
November–April
(blue), April–
November (red),
and year-round
(yellow).
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Influenza reaches peak prevalence in
winter:Northern and Southern Hemispheres have
winter at different times of the year, there are actually
two different flu seasons each year.
People are more indoors in Winter: this promote
person to person spreading
Increased travel due to the Northern Hemisphere
winter holiday season may also play a role.
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In addition cold temperatures lead to drier air, which
may dehydrate mucus, preventing the body from
effectively expelling virus particles.
The virus also survives longer on surfaces at colder
temperatures .
 An alternative hypothesis to explain seasonality is an
effect of vitamin D deficiency on immunity to the
virus(no sun or UV radiation). This idea was first
proposed by Robert Edgar Hope-Simpson in 1965.
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EPIDEMIC AND PANDEMIC SPREAD
ANTIGENIC SHIFT, OR REASSORTMENT, CAN RESULT
IN NOVEL AND HIGHLY PATHOGENIC STRAINS OF
HUMAN INFLUENZA
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Antigenic drift creates
influenza viruses with
slightly modified
antigens, while
antigenic
shift generates viruses
with entirely novel
antigens.
In any given year some
strains can die out while
others
create epidemics, while
yet another strain can
cause a pandemic.
The morbidity is Typically between three and five
million cases of severe illness per hemisphere and up
to 500,000 deaths worldwide.
 more than 200,000 hospitalizations are directly
associated with influenza every year.
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INFLUENZA STRUCTURE
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8 segments of singlestranded RNA
Segments combine
with nucleoprotein
(NP) to form the
ribonucleoprotein
core
M1 matrix protein
surrounds the core
Lipid coat surrounds
the matrix
Embedded in the
lipid membrane are 2
important viral
proteins:
hemaglutinin (HA)
and neuraminidase
(NA)
HEMAGGLUTININ
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Structure: trimer of
“lollipops” with fibrous stem
anchored in the membrane
and globular protein sphere
containing the sialic acid
receptor site
Function: Sialic acid
receptor sites bind to host
cell’s glycoproteins allowing
for infection to occur
NEURAMINIDASE
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Structure: Box-shaped
tetramer with stalk that
anchors it to the membrane
Function: Cleaves off sialic
acid molecules from the
surface of cells thereby
preventing infected cells
from “recapturing” budding
virus molecules (more on
this later…)
INFLUENZA REPLICATION
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Virus is taken into cell through
receptor mediated endocytosis
pH drops and ribonucleoprotein
is released into the cytoplasm
and enters the nucleus
Negative sense vRNA is
transcribed to mRNA and cRNAto do this, caps from host mRNA
are used as primers and PB1,
PB2, and PA make up the
reverse transcriptase
Once packaged (mechanism
unknown), the virus exits the
cell, with the help of NA
Cell dies from lack of viable
mRNA
PATHOGENESIS
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A person becomes infected when they inhale
microdroplets containing the virus
Upper and lower respiratory tract epithelial cells have
sialic acid molecules to which the HA binds
As the virus causes the cells to die, inflammation occurs
– a cough reflex results thereby spreading the virus
again
More severe infections (i.e. pneumonia) are sometimes
associated with Influenza because of the increased
susceptibility to other infections as a result of a
damaged airway
The pathogenicity and virulence of the influenza virus is
determined by several interacting factors
Host factors
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Presence of target receptors
on host cells
Availability of enzymes in
host cells which are essential
for viral entry and replication
State of immunocompetence
of the individual host
Specific immunity against
certain viral epitopes in the
individual host and target
population
Ability of the immune system
to control the viral replication
effectively without causing
serious collateral damage for
the host by its inflammatory
response
Viral factors
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Ability to bind to host cells
Ability to bind to host cells
Ability of virus shedding
Restriction of cytopathogenic
effects to allow for an appropriate
balance between viral replication
and control by the host
Escape from immunosurveillance
by evolution of antigenic variation
driven by selective pressure of the
immune response
Escape from immunosurveillance
by recombination with different
virus strains from zoonotic disease
VIRAL ENTRY: HOW DOES THE VIRION
ENTER THE HOST?
 Virus
infection is spread via respiratory
droplets
 The virus particles binds to cells of the
respiratory epithelium which are rich in
viral receptors.
 Neuraminidase present on the virus
particles aid the infectious process by
releasing virus particles which have been
bound by the mucous present on the
surface of epithelial cells
WHERE DOES THE PRIMARY REPLICATION
OCCUR?
Cellular proteases are often required to cleave
viral proteins to form the mature infectious virus
particle
 Additional factors to entry receptors can
determine the site of viral replication
 In humans, the replication of the influenza virus
is generally restricted to the epithelial cells of the
upper and lower respiratory tract
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HOW DOES THE INFECTION SPREAD
THE HOST?
IN
Once influenza has efficiently infected respiratory
epithelial cells, replication occurs within hours and
numerous virions are produced.
 Infectious particles are preferentially released
from the apical plasma membrane of epithelial cells
into the airways by a process called budding.
 This favors the swift spread of the virus within the
lungs due to the rapid infection of neighboring cells.
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FLU INCUBATION PERIOD: REFERS TO THE
TIME IT TAKES FROM EXPOSURE TO THE
INFLUENZA VIRUS UNTIL THE BEGINNING OF
OBSERVABLE SYMPTOMS.
 The
flu incubation period is usually one to
four days.for H1N1, it may be about four to
seven days.
 The flu incubation period is often shorter for
a person in poor health since his or her body
is already in a weakened state and less able
to fight the virus. During this period, the
person may show no symptoms.
HOST DEFENSES
Interferon signals for cells to produce PKR which
inactivates eIF2 and inhibits protein synthesis
 BUT…Influenza’s NS1 protein binds to dsRNA
which keeps PKR inactivated
 Anti-HA antibodies bind and stay with the virus
as it makes its way through the cell and
somehow interferes with the replication process
 Anti-NA antibodies stop the molecule from
shaving off the sialic acid residues
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CLINICAL FEATURES
disease is usually most severe in very young children (under 5
years of age):lack antibodies to the influenza virus because of no prior
exposure.
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addition, the small diameter of components of the respiratory tract
in the very young also means that inflammation and swelling can lead
to blockage of parts of respiratory tract, sinus system or Eustachian
tubes.
SYMPTOMS AND COMPLICATIONS
1. Uncomplicated influenza
 Fever (38 - 40 degrees C)
 Myalgias, headache
 Ocular symptoms - photophobia, tears, achea
 Dry cough, nasal discharge
 H1N1 strain, the 2009 "swine flu", also gives rise
to gastro-intestinal symptoms (e.g. vomiting,
diarrhea)
2. PULMONARY COMPLICATIONS, SEQUELAE:
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Croup (acute laryngotracheobronchitis) in young
children - symptoms include cough (like a barking
seal), difficulty breathing, stridor (crowing sound
during inspiration)
Primary influenza virus pneumonia
Secondary bacterial infection: This often involves
Streptococcus pneumoniae, Staphylococcus aureus,
Hemophilus influenzae
The build up of fluids and lack of mucociliary
clearance in the respiratory tract provide a good
environment for bacterial growth.
lications often occur in patients with underlying
chronic obstructive pulmonary or heart disease. The
underlying problems may not have been recognized
prior to the influenza infection.
3. NON-PULMONARY COMPLICATIONS OF INFLUENZA:
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Myositis
Cardiac complications
EncephalopathyReye's syndrome:The effects of influenza virus infection
on the liver and brain are particularly serious. In the liver
fatty deposits are seen while in the brain edema occurs.
Guillain-Barré syndrome (acute idiopathic polyneuritis)
It is an autoimmune disease that can follow a viral or
bacterial infection.
The major causes of influenza-associated death are
bacterial pneumonia and cardiac failure. Ninety per cent of
deaths are in people over 65 years of age.
CLINICAL DIAGNOSIS
The clinical picture of influenza is
nonspecific.
 Influenza-like illness can be caused by many
microbial agents other than influenzavirus,
such as adenovirus, parainfluenza viruses,
coronavirus, Mycoplasma pneumoniae,
Chlamydia pneumoniae, beta-hemolytic
streptococcus.
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LABORATORY DIAGNOSIS
 Since
the clinical
picture of influenza
is nonspecific, its
specific diagnosis
must be confirmed
by laboratory tests.
 This is usually made
by virus isolation,
identification of
specific antigens or
antibody rise.
TREATMENT
Generally, anti-viral drugs work optimally when taken within
a few days of the onset of symptoms.
Certain drugs are used in uninfected individuals to guard
against infection.
Four influenza antiviral agents are available
: amantadine, rimantadine, zanamivir and oseltamivi
These drugs fall into categories as either M2-inhibitors
(admantane derivatives) or neuraminidase inhibitors as
illustrated in the following table.
CON’T
Rimantadine and amantadin
 amantadine is effective only against influenza A, not
against influenza B. A derivative of amantadine,
rimantadine , can also be used as amantadine but
has fewer side effects than it. Note that the vaccine is
still preferred over these drugs in the prevention of
influenza.
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Oseltamvir (Tamiflu) and zanamivir (Relenza)
are also used for the treatment and prevention of
influenza. that act by inhibiting the release of
virus from infected cells. This limits the
infection by reducing the spread of virus from
one cell to another. These drugs are effective
against both influenza A and B viruses in
contrast to amantadine, which is effective only
against influenza A viruses.
PREVENTION
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Reasonably effective ways to reduce the
transmission of influenza include good personal
health and hygiene habits such as: not touching
your eyes, nose or mouth;
hand washing
covering coughs and sneezes
avoiding close contact with sick people
Avoiding spitting
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According to the WHO, you can decrease your chance
of contracting the flu virus by taking the following
steps:
Get yourself (or family members age 6 months and
older) vaccinated against current strains of influenza,
if possible.
Keep your distance from people who show symptoms
of influenza-like illness, such as coughing and
sneezing (trying to maintain a distance of about 1
metre if possible);
Clean your hands thoroughly with soap and water, or
cleanse them with an alcohol-based hand rub on a
regular basis (especially if touching surfaces that are
potentially contaminated);
Avoid touching your mouth, nose and eyes as
much as possible;
 Reduce the time spent in crowded settings if
possible;
 Improve airflow in your living space by opening
windows;
 Practice good health habits (including adequate
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INFLUENZA VACCINES
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Whole virus vaccines: inactivated forms of
virus with the predicted HA, are grown in
embryonated eggs
Subunit vaccine: uses both HA and NA
subunits extracted from recomibinant virus
forms
Split-virus vaccines: purified HA (lessens the
side-effects)
Recommended for health care workers,
elderly/ people in nursing homes, asthmatics,
chronic lung disease patients, some pregnant
women, and anyone who is susceptible to
infection
SOURCES
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http://www.cdc.gov/ncidod/hip/INFECT/flu_acute.htm#table
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http://microbiology.mtsinai.on.ca/bug/flu/flu-bug.shtml
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http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Influenza.html
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http://www.sbimc.org/2000/spring/fiddian-slides/
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http://microvet.arizona.edu/Courses/MIC419web/Case4flu.html
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http://www.tulane.edu/~dmsander/WWW/335/Orthomyxoviruses.html
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http://www.psc.edu/science/Herlocher/Herlocher.html
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http://www.cs.bsu.edu/homepages/dmz/david/replicate.html
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http://web.uct.ac.za/depts/mmi/jmoodie/welcome1.html
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http://www.goshen.edu/bio/Biol206/Biol206LabProject/Influenza/SoniaRa
chel/page.html
Levine, Arnold J. Viruses 1992, New York p. 155-175
Sompayrac, Lauren How Pathogenic Viruses Work 2002, Sudbury, MA p.
19-24