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8/3/2019 Replication of the Influenza Virus
1/11
Replication of the Influenza Virus
Viruses can only replicate in living cells. Influenza infection and replication is a multi-step process: firstly the virus
has to bind to and enter the cell, then deliver its genome to a site where it can produce new copies of viral
proteins and RNA, assemble these components into new viral particles and finally exit the host cell.
Influenza viruses bind through hemagglutinin onto sialic acid sugars on the surfaces of epithelial cells; typically in
the nose, throat and lungs of mammals and intestines of birds (Stage 1 in figure 1). After the hemagglutinin is
cleaved by a protease, the cell imports the virus by endocytosis.
Once inside the cell, the acidic conditions in the endosome cause two events to happen: first part of the
hemagglutinin protein fuses the viral envelope with the vacuole's membrane, then the M2 ion channel allows
protons to move through the viral envelope and acidify the core of the virus, which causes the core to dissemble
and release the viral RNA and core proteins. The viral RNA (vRNA) molecules, accessory proteins and
RNA-dependent RNA polymerase are then released into the cytoplasm (Stage 2). The M2 ion channel is blocked
by amantadine drugs, preventing infection.
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These core proteins and vRNA form a complex that is transported into the cell nucleus, where the
RNA-dependent RNA polymerase begins transcribing complementary positive-sense vRNA (Steps 3a and b). The
vRNA is either exported into the cytoplasm and translated (step 4), or remains in the nucleus. Newly synthesised
viral proteins are either secreted through the Golgi apparatus onto the cell surface (in the case of neuraminidase
and hemagglutinin, step 5b) or transported back into the nucleus to bind vRNA and form new viral genome
particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading cellular mRNA
and using the released nucleotides for vRNA synthesis and also inhibiting translation of host-cell mRNAs.
Negative-sense vRNAs that form the genomes of future viruses, RNA-dependent RNA polymerase, and other viral
proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in the cell
membrane. The vRNA and viral core proteins leave the nucleus and enter this membrane protrusion (step 6). The
mature virus buds off from the cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and
neuraminidase with this membrane coat (step 7). As before, the viruses adhere to the cell through hemagglutinin;
the mature viruses detach once their neuraminidase has cleaved sialic acid residues from the host cell. Drugs that
inhibit neuraminidase, such as oseltamivir, therefore prevent the release of new infectious viruses and halt viral
replication. After the release of new influenza viruses, the host cell dies.
Figure 2. (A) If a cell is infected with two different influenza viruses, the RNAs of both viruses are copied in the
nucleus. When new virus particles are assembled at the plasma membrane, each of the 8 RNA segments may
originate from either infecting virus. The progeny that inherit RNAs from both parents are called reassortants. (B)
The underlying concern is that swine are susceptible to a wide variety of influenza viruses, and are thought to
make excellent `mixing vessels for influenza stains. Although the odds of it happening are probably very low, the
worry is that a pig could be infected by two different influenza strains simultaneous, and a reassortment of the
viruses could take place. The result could be a new, or mutated, flu virus.
Because of the absence of RNA proofreading enzymes, the RNA-dependent RNA polymerase that copies the viral
genome makes an error roughly every 10 thousand nucleotides, which is the approximate length of the influenza
vRNA. Hence, the majority of newly manufactured influenza viruses are mutants; this causes "antigenic drift",
which is a slow change in the antigens on the viral surface over time. The separation of the genome into eight
separate segments of vRNA allows mixing or reassortment of vRNAs if more than one type of influenza virus
infects a single cell (see figure 2). The resulting rapid change in viral genetics produces antigenic shifts, which are
sudden changes from one antigen to another. These sudden large changes allow the virus to infect new host
species and quickly overcome protective immunity. This is important in the emergence of pandemics.
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Influenzavirus A
This genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of
influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in
domestic poultry or give rise to human influenza pandemics. The type A viruses are the most virulent human
pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be
subdivided into different serotypes based on the antibody response to these viruses. The serotypes that have
been confirmed in humans, ordered by the number of known human pandemic deaths, are:
H1N1, which caused Spanish Flu in 1918, and Swine Flu in 2009
H1N2, endemic in humans, pigs and birds
H2N2, which caused Asian Flu in 1957
H3N2, which caused Hong Kong Flu in 1968
H5N1, which caused Bird Flu in 2004
H7N2 H7N3 H7N7, which has unusual zoonotic potential
H10N7
^ Back to Top
Influenzavirus B
This genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common
than influenza A. The only other animals known to be susceptible to influenza B infection are the seal and the
ferret. This type of influenza mutates at a rate 23 times slower than type A and consequently is less genetically
diverse, with only one influenza B serotype. As a result of this lack of antigenic diversity, a degree of immunity to
influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not
possible. This reduced rate of antigenic change, combined with its limited host range (inhibiting cross
speciesantigenic shift), ensures that pandemics of influenza B do not occur.
Influenzavirus B is the only species of the genus influenzavirus B. The wide diversity
in shapes and sizes of viruses are called morphology. Its protective protein shell,
capsid, is enveloped; while the entire virion consists of an envelope, a matrix protein,
a nucleoprotein complex, a nuecleocapsid, and a polymerase complex. Influenzavirus
B comes in different shapes, usually spherical or filamentous.
As far as humans know or have experienced is that Influenzavirus B can only be
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found in seals and humans, or it is only known for causing diseases on these two
species. Compared to influenzavirus A, it mutates three times slower, but humans
still cannot have a long lasting immunity for it. The seasonal outbreak of flu is usually
caused by both influenzavirus A and influenzavirus B. As the two are very similar,
they cause the same spectrum of disease, only that influenzavirus B is not as
powerful and does not cause a pandemic. So the international outbreak of flu must
not be caused by influenzavirus B.
The structures of influenzavirus B is very similar to the structure of that in
influenzavirus A, it would be barely possible to distinguish a influenzavirus A and
influenzavirus B under the electron microscope. But when looked carefully, it can be
visualized that influenzavirus A has only three membrane proteins while the
influenzavirus B has four.
^ Back to Top
Influenzavirus C
This genus has one species, influenza C virus, which infects humans, dogs and pigs, sometimes causing both
severe illness and local epidemics. However, influenza C is less common than the other types and usually only
causes mild disease in children.
Influenzavirus C is very different from influenzavirus A and influenzavirus B. This virus
possesses a receptor-destroying enzymatic activity. For the other twoinlfuenzaviruses, they have proteins on their surface which match with the host cells
surface, and thus are allowed to enter the host cell. But influenzavirus C has enzymes
on its surface which catalyses the breakdown of the receptors on the surface of the
host cells, making it more convenient to enter a host cell and replicate.
Influenzavirus C can be found in humans and pigs, they rarely cause influenza in
these two organisms, but can be deadly and may cause local epidemics.
Causes of the 1918 flu epidemic
The 1918 flu pandemic, also known as the Spanish Flu, remains the single most
devastating epidemic in recorded human history, with estimates between 40 and 80
million deaths. Despite the severity of the disease, little is known about the causes,
progression and eventual dissipation of the disease. However, some evidence has helped
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researchers better understand how the disease originated and why it progressed so
quickly.
The 1918 Spanish Flu was an Influenza A strain of the H1N1 subtype. Influenza A is most
well-known as the avian strain of influenza, which also includes the H5N1 subtype thathas received recent publicity as the "avian bird-flu". The H1N1 strain is generally not
among the most virulent or fatal of flu strains. In the last few years, variants of H1N1 have
been responsible for over half of all flu infections worldwide, but a far smaller proportion of
deaths.
The most fascinating feature of the flu of 1918 may shed a great deal of insight into its
origin and rapid spread. Most influenza strains target the immuno-compromised, the
young, and the elderly. In these subpopulations, the immune system cannot effectively
fight the influenza virus and, as a result, infection ensues. However, the Spanish flu
featured a "cytokine burst" at the area of infection, which drastically changed how this flu
interacted with the human host, targeting the healthiest members of the population.
Cytokines are special cellular signalling molecules and many are involved with the human
body's immune response. In victims of the Spanish flu, the virus actually causes levels of
cytokines to spike dramatically, increasing the body's immune response. Leukocytes,
or white blood cells, are recruited by the cytokine storm and cause damage to the tissue at
the site of infection. For most humans, the infection site would be the lungs as the virus
would be caught from air-borne particles. The lung tissues would be destroyed and fluids
would fill the lung and impair breathing.
The use of the body's own immune system as a weapon changes the infection pattern of
the 1918 flu. Humans with the strongest immune systems, healthy 19-40 year olds, were
most susceptible to infection and the resulting tissue damage. The young, elderly and
immuno-compromised could not generate the powerful cytokine storms that weakened
their healthier counterparts.
With this in mind, it is easy to see how the disease could spread in the world of 1918.World War I was nearing its close, but soldiers, medics and
statesmen were still traveling abroad with greater frequency than any other time.
Most of the armed forces of the countries involved in World War I were young men,
fitting the description of that group most susceptible to the influenza. The wartime
stress and horrid living conditions for soldiers across Europe further exacerbated the
spread of the flu and the resulting casualties.
New transportation technology made travel easier for everyone, setting the stage fora global outbreak. Japan and American Somoa were among the few nations that took
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extreme measures to quarantine infected individuals and close ports to travelers
from other countries. As a result, Somoa didn't report a single death and Japan had a
much lower mortality rate than any other Eastern Asian nation.
As our world continues to grow into a global economy, it is important that we are
aware of the dangers of global outbreaks of disease. There is a great deal to learn
from the 1918 flu epidemic that could prove useful in protecting humanity from
future devastation. From understanding the mechanism of pandemic flu infections,
including the cytokine storms and infection of the healthy, to a better model of
disease travel in a connected world, the origins of the flu of 1918 provide greater
insight into epidemic creation and spread.
Involve changes in the influenza polymerase
A polymerase of an influenza virus: composed of viral proteins PB1, PB2, and PA,
assembles with viral RNA and nucleoprotein (NP) to mediate transcription and
replication of the viral genome.
General acknowledgements on adaptive mutation
Viruses isolated from birds generally contain polymerases with the
avian-signature glutamic acid at amino acid 627 in the PB2 subunit. These
polymerases have restricted activity in human cells. An adaptive change in
this residue from glutamic acid to the human-signature lysine confers high
levels of polymerase activity in human cells.
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glutamic acid-to-lysine mutation facilitates escape from an inhibitory factor
that restricts the function of avian-derived polymerases in human cells .The
identity of the putative inhibitor and the molecular basis for the activity
associated with changes at amino acid 627 have not yet been established
genetic reassortment
allows new viruses to evolve under both natural conditions and in artificial
cultures
is the mixing of the genetic material of one species into new combinations in
different individuals: e.g. When two different Influenza A viruses co-infect the
same host cell, new virions are released that contain segments from both
parental strains.
can only occur between influenza viruses of the same type. We dont know
why influenza B and C cannot exchange RNA segments---- the reason is
probably linked to the packaging mechanisim that ensures that each influenza
virion contains at least one copy of each RNA segment
Process of genetic reassorment
When an influenza virus infects a cell, the individual RNA segments enter the
nucleus. There they are copied many times to form RNA genomes for new
infectious virions. The new RNA segments are exported to the cytoplasm, and
then are incorporated into new virus particles which bud from the cell.
If a cell is infected with two different influenza viruses, the RNAs of bothviruses are copied in the nucleus. When new virus particles are assembled at
the plasma membrane, each of the 8 RNA segments may originate from
either infecting virus. (The progeny that inherit RNAs from both parents are
called reassortants. )
a cell that is co-infected with two influenza viruses L and M. The infected cell
produces both parental viruses as well as a reassortant R3 which inherits one
RNA segment from strain L and the remainder from strain M.
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Antigenic shift occurs only in influenza virus A
infects more than just humans
the process by which at least two different strains of a influenza virus (or
different viruses), combine to form a new subtype having a mixture of the
surface antigens of the two original strains. Antigenic shift is a specific case of
reassortment or viral shift that confers a phenotypic change.
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Antigenic drift
How influenza viruses evade infection-fighting antibodies by constantly
changing the shape of their major surface protein, antigen
Dr. Yewdell(Scott Hensley, Ph.D., Jonathan W. Yewdell, M.D., Ph.D., ).
---------According to the prevailing theory, drift occurs as the virus is passed from
person to person and is exposed to differing antibody attacks at each stop. With
varying success, antibodies recognize one or more of the four antigenic regions in
hemagglutinin, the major outer coat protein of the flu virus. Antibodies in person A,
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for example, may mount an attack in which antibodies focus on a single antigenic
region. Mutant viruses that arise in person A can escape antibodies by replacing one
critical amino acid in this antigen region. These mutant viruses survive, multiply and
are passed to person B, where the process is repeated.
natural mutation over time of known strains of influenza (or other things, in a
more general sense) which may lead to a loss of immunity, or in vaccine
mismatch
(Genetic drift)
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change in the frequency of a gene variant (allele) in a population due to
random sampling(related to statistics).The alleles in the offspring are a
sample of those in the parents, and chance has a role in determining whether
a given individual survives and reproduces. A population's allele frequency is
the fraction of the copies of one gene that share a particular form.
main pt of antigenic drift and antigenic shiftnew forms antigen is different from the old antigen, antibodies can no longer bind to the receptors and
viruses with these new antigens can evade immunity to the original strain of the virus. When such a
changes occurs, people who have had the illness in the past will lose their immunity to the new strain and
vaccines against the original virus will also become less effective
new forms of antigen binding site on antibodies cannot bind with the new forms of antigen of the same
virus anymore, since the body may not encounter this new form of antigen before
and then blahblahblah
this is the mechanisim for antigenic dirft and shift