Download Avien Influenza Virus and Mutation

Avian influenza virus
and mutation
 Köksal öksüz
Bacterial cell
Animal cell
Plant cell
Gram-negative cell wall
Animal cell wall
Gram-positive cell wall
Plant cell wall
 Graphic of Viral Entry into Animal Cells: virus
attachment to cell surface (adsorption) and virus
entry into cell. Picture shows translocation, pore
formation, receptor mediated endocytosis using
clathrin coated vesicles and membrane fusion.
Some viruses can use more than one strategy.
Other means are also employed.
 1. NAKED VIRUS - TRANSLOCATION: particle
crosses cell membrane intact (cf Principles of
Molecular Virolgy, 3rd Edition, Alan J. Cann,
Academic Press p 117)
 2. NAKED VIRUS - GENOME
INJECTION: virüs hücre yüzeyine tutunur
ve genomunu plazma membranına açılmış
bir por aracılığı ile bırakır (Bacteriophages,
which attack bacterial cells, also inject
their genomes and may use molecular
"syringes" to do so, T4 phages injecting ).
 3. NAKED VIRUS - ENDOCYTOSIS: virüs
hücre yüzey moleküllerine tutunur ve
clathrin kaplı bir çukur oluşur ve onun içine
düşer. Çukur tamamen virüsü kaplar ve
sonunda clathrin kaplı bir kafes gibi
kapanır. Bu molekül kafesi kısa bir süre
sonra pervaneye benzeyen komponentlere
ayrılır. Serbest kalan kese içerdiği viron’u
endosoma taşır. Son aşamadai se viral
komponentler açığa çıkar. Adenovirus
 4. ENVELOPED VIRUS - ENDOCYTOSIS
& MEMBRANE FUSION: virus enters cell
by receptor mediated endocytosis. The
cell membrane merges (fuses) with the
endosome membrane and so the virus
components are released. The virus
shown here is an influenza virus,
Influenza virus life cycle illustration
 5. ENVELOPED VIRUS - MEMBRANE
FUSION: virus enters the cell when its
outer membrane fuses with the plasma
membrane at the cell surface. The viral
contents are then spilled into the
cytoplasm of the cell. This example is HIV,
which is unusual in having a conical core
(most viral cores tend to be more
spherical). HIV illustrations.
next stage
Bacteriophages
T4 phages injecting
T4 phages injecting

adenovirus
Genetic modification between
human flu virus and
avian influenza (bird flu) H5N1
 EXPLANATION OF PICTURE The green core ( RNP ribonucleoprotein ) contains the genetic information of the virus
wrapped up in protein. This combination of gentic material and
protein is called the nucleocapsid. In influenza, the nucleocapsid is
helical. The genetic information is stored as single stranded -ve
sense RNA. The full complement of genetic information is called the
genome and in influenza the genome is divided into eight segments.
These segments are assumed to link together ( possibly in an
ordered fashion ) to form a helix when the virus assembles at the
cell surface. Overlying the nucleocapsid is a layer of matrix protein,
M1, shown in purple. Overlying the matrix is the viral envelope
(blue-green and edged in yellow) derived from the host cell
membrane ( the nucleocapsid and the matrix proteins become
wrapped in cell membrane as they bud from the infected cell ). The
characteristic "spikes" of the influenza virus are haemagglutinin.
They radiate all over the surface and are interspersed (in some
types) by clusters of neuraminidase. These (HA and NA) molecules
are thought to pass through the envelope and interact with the
underlying matrix protein, M1
INFLUENZA VIRUS-TYPES
A- Birds, mammals (including humans, pigs, horses,
sea mammals etc.)
B- Humas
C- Humans. Pigs
 İnfluenza A ve B virüsleri iki yüzey glikoproteini
taşır, Hemagglutinin (HA) ve Neuraminidase (NA).
Her iki protein; aynı alıcı hücre molekülü olan
sialik asidi tanımlar ve seçici olarak ona bağlanır.
HA, virüs infeksiyonunu başlatmak için hedef
hücrenin üzerindeki sialik asit içeren reseptöre
bağlanır, oysa NA; hücresel reseptörlerden sialik
asiti koparır ve hücre dışı geri kazandırıcıdır, yeni
oluşan virüslerin serbest bırakılmasını kolaylaştırır
ve komşu hücrelere enfeksiyonun sıçramasını
teşvik eder. Bir çok araştırma glikoproteinlerin
arasındaki reseptör bağlayıcı ve reseptör yıkıcı
aktivitenin optimum etkileşiminin olmasının virus
replikasyonu için gerekli olduğunu açıklamıştır.
Type A Influenza Surface Antigens
Surface Antigen Subtype
Haemagglutinin:
1 2 3
human   
Equine

Swine 

Avian   
Neuraminidase:
1 2 3
Human  
Equine
Swine  
Avian   
4 5 6 7 8 9 10 11 12 13 14 15

           
4 5 6 7 8 9
 
     
 H5N1
 İnfluenza A H5N1, ilk kez güney afrikada
1961’de balıkçıllardan izole edilmiş olmakla
birlikte, patojenitesi yüksek kuş gribi olarak
daha önceden, ilk kez 1878’de İtalya’da
tanımlanmıştır. Kuş gribi virüsünün doğal
rezervuarı, yeşilbaş ördeklerdir. Ve
enfeksiyona en en dayanıklı olan kuşlarda
bunlardır. Virüsleri çok uzağa taşımalarına
karşılık, yalnızca hafif hastalıklar geçirirler.
Mutasyon sonucu oluşan H1N1 1918-1919
yıllarında 40-50 milyon insanı öldürdü.
İnfluenza virüsü, solunum epitelia hücrelerine baştan başa bulaşmak
ve geçişi kolaylaştırmak için birkaç mekanizmaya sahiptir
A- virüsün yüzeyindeki HA proteinleri hücrenin yüzeyindeki
tabakalaşmış sialik asite bağlanır
B- bu komplexin oluşumu hücrenin tamamen virüsü kaplamasını
tetikler
C- viral RNA hücre nukleusuna girer ve viral replikasyon başlar
D- yeni oluşmuş hücrenin yüzeyindeki NA; hücrenin yüzeyindeki sialik
asit moleküllerini koparır, virüsün ortaya çıkmasına ve solunum
organı’nın mukoz astarı boyunca yayılmasına olanak tanır.
Viral replikasyon hücre ölüm prosesini başlatır, bu; virüsün ortaya
çıkmasından ( replikasyondan sonra) birkaç saat sonra başlar.
 BIRD FLU REASSORTMENT GRAPHIC: illustration
above shows reassortment of viral RNA segments in a
cell infected by two strains of influenza virus (human
and bird flu) leading to a new and potentially
dangerous strain that could spread easily from human
to human and so trigger a deadly worldwide epidemic.
Such genetic mixing might occur in pigs, since a pig
might be infected by both strains and then pass the
new virus on to humans. Alternatively, a person might
become infected with bird flu and human flu and start
an epidemic of the novel virus
 END
 Influenza virus life cycle illustration
 Influenza A virus has its RNA genome (genetic
material) split into 8 segments. If two different
viral types infect the same cell, then segments
from both types can get jumbled together (they
reassort) as the new virus particles are
assembled. Consequently, new viral strains can
emerge that contain a mixture of the parental
genes. Image shows two different viral strains
(BLUE genome at upper right and ORANGE
genome at upper middle) infecting the same cell
(at lower right). During replication, new viral
particles may emerge that contain segments
sourced form both the BLUE and the ORANGE
strains. The new strain (BLUE & ORANGE
STRIPED genome, shown at left) has the
potential to spread rapidly.
 CELL ENTRY: At upper right, a BLUE influenza virus
particle (representing an avian flu virus) is shown landing
on the cell surface. The virus docks with cell membrane
when the red spikes (haemagglutinin, shown in red) link to
molecules on the cell surface. The cell surface folds
inwards causing the virus particle to sink into the cell. The
virus sinks deeper into the cell until it is completely
wrapped up in cell membrane. The resulting membranous
"bubble" (or vesicle) breaks free from the surface of the
cell and transports its contained virus into the cell. The
netlike structure beneath the docking virus and the cagelike structure around the resultant vesicle represent
clathrin, a protein that forms an external scaffold that
causes the cell membrane to invaginate and finally form
the vesicle (this entry mechanism is called receptor
mediated endocytosis please see our VIRAL ENTRY
graphic). Further to the left an ORANGE influenza virus
particle (representing a human flu virus) is shown landing
on the cell surface.
 UNCOATING OF VIRUS AND RELEASE OF GENOME
INTO CELL: The clathrin coat is then lost and the virus
in its naked vesicle can be seen half out of frame at the
right of the image. The engulfed virus then appears in an
endosome (the large irregular yellow vesicle). It is more
acidic in the endosome and this modifies the
haemagglutinin spikes. The altered haemagglutinin
draws the membranes of the virus and endosome
together and they merge, creating a hole through which
the viral contents are poured into the cytoplasm. These
contents include the viral matrix protein (purple) and the
nucleocapsid (BLUE segments). Some matrix protein is
shown travelling to the nucleus. The nucleocapsid
segments, which contain the viral genetic information,
migrate to the nucleus. They move into the nucleus via
nuclear pores (the flower like structures on the curved
surface of the nucleus) and so deliver the viral genome
to the nucleus (which contains the cell's own genetic
material).
 INSIDE THE NUCLEUS: In the nucleus, the viral genetic
material (-ve sense RNA) produces viral messenger RNAs of
various kinds (vmRNA) which travel out through the nuclear
pores. (Messenger RNA, or mRNA, carries the genetic
information that is used to direct protein maunfacture.) Some
vmRNA directs the synthesis of nucleoprotein (green dots)
that travel back into the nucleus. Other vmRNA directs the
production of matrix protein (purple dots) shown emerging
from a viral polyribosome (several ribosomes strung together
along a length of viral mRNA) in the middle of the picture.
Some matrix protein travels to the nucleus and some collects
beneath the cell membrane. Other vmRNAs direct the
production of external (transmembrane) viral proteins. The
manufacture of such "external" proteins follows a different
route. Production starts in the rough endoplasmic reticulum
and progresses through the Golgi apparatus. The
haemagglutinin (red) is shown progressing through the
Golgi at lower left, finally being discharged onto the cell
surface from a vesicle (the sphere containing red dots that is
delivering its contents onto the cell surface through a hole).
The neuraminidase (yellow) is shown (for clarity) going
through the Golgi in parallel but above the haemagglutinin.
 NEW VIRAL RNA SEGMENTS: In the
nucleus, the viral -ve sense genome also
produces +ve sense copies of itself. These
are then used to create further copies of
the viral genome. These new -ve sense
viral genomic RNAs become associated
with nucleoproteins and some matrix
proteins that have migrated into the
nucleus. Such newly formed
nucleocapsids and their associated M
proteins exit the nucleus via nuclear pores
(BLUE and ORANGE segments can be
seen streaming across the cell).
 VIRAL ASSEMBLY AT CELL SURFACE: Just beneath the cell
surface, these individual BLUE and ORANGE ribonucleoprotein
segments are shown associating together to form the helical
nucleocapsid (the BLUE and ORANGE barrel-like structure).
Around the new nucleocapsid, the matrix proteins are shown
collected beneath the cell membrane (the haze of purple
particles marked), while above the cell membrane,
haemagglutinin and neuraminidase have coated the surface.
With all these viral elements now in place, the newly forming
virus particle (which contains segments derived from both the
BLUE and ORANGE strains) can begin to take shape and to
bud from the cell surface. The cell membrane that envelopes
the emerging nucleocapsid and matrix protein becomes the
viral envelope (complete with projecting spikes) and the virus
particle is released. The new virus particle is now ready to
infect another cell. Because it contains a new mix of genes, this
reassortant can pose seroius dangers. This dramatic change in
the genotype is called antigenic shift to distinguish it from the
more minor changes that occur due to mutation or poor fidelity
RNA copying, which are called antigenic drift.
 Human Immunodeficiency Virus (HIV) particle (upper
right) attaches to cell surface. The viral envelope merges
with the cell plasma membrane (middle) releasing the
matrix shell and core (purple bullet-shaped structure
containing the viral genome) into the cell. The viral RNA
(yellow string-like structure in core) is converted into viral
DNA (red string-like structure in core) by the enzyme
reverse transcriptase (green sphere). The viral genome
is delivered to the nucleus (brownish sphere at bottom)
and enters through a nuclear pore (flower-like opening).
Once inside the nucleus, the viral DNA joins (integrates)
with the host cell DNA. The viral DNA then directs the
production of viral RNA which exits the nucleus through
nuclear pores. Some viral RNA goes to form a new viral
genome (yellow lump attached to underside of cell
membrane at left) while other viral RNA directs the
production of new viral proteins via ribosomes (3 brown
spherical objects in middle of cell). The new viral
components (genome + proteins) assemble at the cell
surface (left) and a new virus particle buds from the cell
(upper left).

Human Immunodeficiency Virus (HIV or AIDS virus): HIV attacks a macrophage (top
middle) and a Helper T Cell (lower left). New virus particles then bud from the
macrophage. A B-lymphocyte (bottom right) gives rise to Plasma Cells (reddish cells
on right) that produce antibodies (Y shaped molecules in red) that bind to HIV. A killer
cell (bottom middle) will attack virus infected cells. The interaction of HIV and the
immune system is very complex and varies over time.

Human Immunodeficiency Virus (HIV or AIDS virus): Human
Immunodeficiency Virus: this illustration shows the external appearance of
the virion. The virus is coated (enveloped) in host cell membrane, which is
drawn as a bluish green semi transparent layer in which various membrane
proteins can be seen floating. The viral knobs (golden projections at the
viral surface) insert into the matrix. These knobs allow the virus to attach to
cells.
HIV cell entry and replication
animation
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