replication of the influenza virus

8/3/2019 Replication of the Influenza Virus

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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

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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.

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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

replication of the influenza virus

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