2. I had a little bird
Its name was Enza
I opened the window
And In-flu-enza
1889–1890 Asiatic or Russian Flu
1 million deaths
1918-1920 Spanish flu
20 to 100 million
1957–1958 Asian Flu
1 to 1.5 million
1968–1969 Hong Kong flu
0.75 to 1 million
1977-1978 Russian flu
2009-2010 Flu Pandemic
18,000
4. Orthomyxoviridae
The Orthomyxoviridae are a family of RNA
viruses that includes five genera:
Influenzavirus A, Influenzavirus B,
Influenzavirus C, Isavirus and Thogotovirus.
The Influenzaviruses cause influenza in
vertebrates, including birds , humans, and
other mammals.
Isaviruses infect salmon; thogotoviruses
infect vertebrates and invertebrates, such
as mosquitoes and sea lice.
7. Structure
Characteristics
Envelope :
2 glycoproteins – hemagglutinin (HA)
neuraminidase (NA)
Membrane protein M2
Matrix protein M1
A + B viruses – 8 different hellical
nucleocaspid segments of RNA
C – 7 genomic segments
9. Ag Shifts
Characteristics
The HA and NA of influenza A virus can undergo
major and minor Ag changes to ensure the presence
of immunologically naïve , susceptible people.
Shifts occur only with influenza A virus , and the
different HAs are designated H1, H2…H16.
The NA of influenza A also undergoes antigenic shifts.
Mutation-derived changes in HA are responsible for
the changes in antigenicity (shifts).
Influenza B virus undergoes only minor antigenic
changes .
This process occurs every 2 to 3 years causing local
outbreaks of influenza A and B infection.
11. Transmission
Pathogenesis
Transmission mainly person to person by
sneezing , coughing , or simply talking .
Virus likes a cool , less humid atmosphere (
winter heating season ).
Extensively spread by school children .
The respiratory tract is the gate opening of
the virus .
Influenza can also be transmitted by
saliva, nasal secretions, feces and blood.
13. Replication
Pathogenesis
Begins with the binding of HA to
sialic acid on cell surface
glycoproteins .
The virus is then transferred to an
endosome through vesicles .
The nucleocapsid travels to the
nucleus , where it is transcribed into
messenger RNA.
The transcriptase uses host cell
mRNA as a primer for viral mRNA
synthesis
14. Replication
The mRNAs are translated into protein in the
cytoplasm.
The HA and NA glycoproteins are processed
by the endoplasmic reticulum and Golgi
apparatus.
The HA and NA are then transported to the
cell surface.
The virus buds selectively from the apical
(airway) surface of the cell as a result of the
preferential insertion of the HA in this
membrane.
Virus is released approximately 8 hours after
infection.
Pathogenesis
16. Pathogenesis
The important Products of
Influenza Gene Segments
Segment Protein Function
4 HA Hemagglutinin, viral attachment protein, fusion protein,
target of neutralizing antibody
5 NP Nucleocapsid
6 NA Neuraminidase (cleaves sialic acid and promotes virus
release)
7 M1 Matrix protein: viral structural protein (interacts with
nucleocapsid and envelope, promotes assembly)
M2 Membrane protein (forms membrane channel and target for
amantadine, facilitates uncoating and HA production)
17. Pathogenesis
Pathogenesis
Incubation period : 1-4 days ( average of 2 days ) .
Adults can be infectious from 1 day before start of
symptoms to 5-7 days after illness starts .
More infectious in children .
The main cause of hospitalization is flu .
The symptoms and time course of the disease are
determined by the extent of viral and immune killing of
epithelial tissue and cytokine action .
Influenza is normally a self-limited disease that rarely
involves organs other than the lung .
Repair of the compromised tissue is initiated within 3 to 5
days of the start of symptoms but may take as long as a
month or more , especially in elderly people .
19. Pathogenesis
Pathogenesis
Influenza initially establishes a local upper respiratory
tract infection . To do so, the virus first targets and kills
mucus-secreting, ciliated, and other epithelial cells,
causing the loss of this primary defense system. NA
facilitates the development of the infection by
cleaving sialic acid (neuraminic acid) residues of the
mucus, thereby providing access to tissue.
Preferential release of the virus at the apical surface
of epithelial cells and into the lung promotes cell-to-cell
spread and transmission to other hosts. If the virus
spreads to the lower respiratory tract, the infection
can cause severe desquamation (shedding) of
bronchial or alveolar epithelium down to a single-cell
basal layer or to the basement membrane.
20. Pathogenesis
Pathogenesis (what else does influenza harm)
Influenza infection promotes bacterial adhesion to
the epithelial cells .
Pneumonia may result from a viral pathogenesis or
from a secondary bacterial infection .
Inflammatory cell response of the mucosal
membrane (monocytes, lymphocytes and few
neutrophils ) .
Submucosal edema .
Hyaline membrane disease .
Alveolar emphysema .
Necrosis of alveolar walls .
21. Pathogenesis and immunology
Interferon and cytokine responses may be
sufficient to control the infection and are
responsible for the systemic “flulike”
symptoms.
T-cell responses are important for effecting
recovery and immunopathogenesis , but Ab
including vaccine induced Ab , can prevent
disease .
Influenza infection depresses macrophage
and T-cell function .
Pathogenesis
24. A brief prodrome of malaise and headache lasting a few hours
Onset fever , chills , severe myalgias , loss of apetite , weakness and fatigue
, sore throat , nonproductive cough .
Recovery within 7 to 10 days Pneumonia , myositis , and Rye syndrome .
26. Epidemiology
Epidemiology
Typically, in a year's normal two flu
seasons (one per hemisphere), there are
between three and five million cases of
severe illness and around 500,000 deaths
worldwide.
Roughly three times per century, a
pandemic occurs, which infects a large
proportion of the world's population and
can kill tens of millions of people .
27. Diagnosis
Diagnosis ,Prevention and
Treatment
Based on the characteristic symptoms.
The season , presence of the virus in
community .
Cell culture in monkey kidney .
Hemagglutination .
Ab inhibition of hemadsorption .
28. Prevention
Vaccine :
Diagnosis ,Prevention and
Treatment
A shot containing killed virus ( inactivated )
given in the arm normally .
Can be also given as nasal spray .
Other :
Keeping good hygiene habits
Covering coughs and sneezes
Staying away of sick people
29. Treatment
Diagnosis ,Prevention and
Treatment
Acetaminophen , antihistamines and
other drugs are used to relieve the
symptoms .
Amantadine and rimantadine inhibit an
uncoating step of influenza A virus but do
not affect the influenza B and C viruses .
Zanamivir and oseltamivir inhibit both A
and B as enzyme inhibitor of
neuraminidase .
I had a little bird , its name was enza , I opened the window and influenza
The M1, M2, and NP proteins are type specific and are therefore used to differentiate influenza A from B or C viruses.
Mutation-derived changes in HA are responsible for the minor ("drift") and major ("shift") changes in antigenicity. Shifts occur only with influenza A virus, and the different HAs are designated H1, H2…H16.
Mutation-derived changes in HA are responsible for the changes in antigenicity (shifts)
All the proteins are encoded on separate segments, with the exception of the nonstructural proteins (NS1 and NS2) and the M1 and M2 proteins, which are transcribed from one segment each.\
The HA has several functions. It is the viral attachment protein, binding to sialic acid on epithelial cell surface receptors; it promotes fusion of the envelope to the cell membrane at acidic pH; it hemagglutinates (binds and aggregates) human, chicken, and guinea pig red blood cells; and it elicits the protective neutralizing antibody response.
Viral replication begins with the binding of HA to sialic acid on cell surface glycoproteins (Figure 57-2). The different HAs (HA1-16) bind to different sialic acid structures. The virus is then internalized into a coated vesicle and transferred to an endosome. Acidification of the endosome causes the HA to bend over and expose hydrophobic fusion-promoting regions of the protein. The viral envelope then fuses with the endosome membrane. The proton channel formed by the M2 protein promotes acidification of the envelope contents to break the interaction between the M1 protein and the NP, allowing uncoating and delivery of the nucleocapsid into the cytoplasm.
Unlike most RNA viruses, the influenza nucleocapsid travels to the nucleus, where it is transcribed into messenger RNA (mRNA). The transcriptase (PA, PB1, and PB2) uses host cell mRNA as a primer for viral mRNA synthesis. In so doing, it steals the methylated cap region of the RNA, the sequence required for efficient binding to ribosomes. All the genomic segments are transcribed into 5'-capped, 3'-polyadenylated (polyA) mRNA for individual proteins except the segments for the M1, M2 and NS1, NS2 proteins, which are each differentially spliced (using cellular enzymes) to produce two different mRNAs
The mRNAs are translated into protein in the cytoplasm. The HA and NA glycoproteins are processed by the endoplasmic reticulum and Golgi apparatus. The M2 protein inserts into cellular membranes. Its proton channel prevents acidification of Golgi and other vesicles, thus preventing acid-induced folding and inactivation of the HA within the cell. The HA and NA are then transported to the cell surface.
Positive-sense RNA templates for each segment are produced, and the negative-sense RNA genome is replicated in the nucleus. The genomic segments associate with polymerase and NP proteins to form nucleocapsids, and the NS2 protein facilitates the transport of ribonucleocapsids into the cytoplasm, where they interact with the M1 protein-lined plasma membrane sections containing M2, HA, and NA. The virus buds selectively from the apical (airway) surface of the cell as a result of the preferential insertion of the HA in this membrane. Virus is released approximately 8 hours after infection.
The mRNAs are translated into protein in the cytoplasm. The HA and NA glycoproteins are processed by the endoplasmic reticulum and Golgi apparatus. The M2 protein inserts into cellular membranes. Its proton channel prevents acidification of Golgi and other vesicles, thus preventing acid-induced folding and inactivation of the HA within the cell. The HA and NA are then transported to the cell surface.
Positive-sense RNA templates for each segment are produced, and the negative-sense RNA genome is replicated in the nucleus. The genomic segments associate with polymerase and NP proteins to form nucleocapsids, and the NS2 protein facilitates the transport of ribonucleocapsids into the cytoplasm, where they interact with the M1 protein-lined plasma membrane sections containing M2, HA, and NA. The virus buds selectively from the apical (airway) surface of the cell as a result of the preferential insertion of the HA in this membrane. Virus is released approximately 8 hours after infection.
Pathogenesis and Immunity
Influenza initially establishes a local upper respiratory tract infection (Box 57-2). To do so, the virus first targets and kills mucus-secreting, ciliated, and other epithelial cells, causing the loss of this primary defense system. NA facilitates the development of the infection by cleaving sialic acid (neuraminic acid) residues of the mucus, thereby providing access to tissue. Preferential release of the virus at the apical surface of epithelial cells and into the lung promotes cell-to-cell spread and transmission to other hosts. If the virus spreads to the lower respiratory tract, the infection can cause severe desquamation (shedding) of bronchial or alveolar epithelium down to a single-cell basal layer or to the basement membrane.
BOX 57-2 Disease Mechanisms of Influenza A and B Viruses
Virus can establish infection of the upper and lower respiratory tract.
Systemic symptoms are caused by the interferon and cytokine response to the virus. Local symptoms result from epithelial cell damage, including ciliated and mucus-secreting cells.
Interferon and cell-mediated immune responses (natural killer and T cells) are important for immune resolution and immunopathogenesis.
Infected people are predisposed to bacterial superinfection because of the loss of natural barriers and exposure of binding sites on epithelial cells.
Antibody is important for future protection against infection and is specific for defined epitopes on hemagglutinin (HA) and neuraminidase (NA) proteins.
The HA and NA of influenza A virus can undergo major (reassortment: shift) and minor (mutation: drift) antigenic changes to ensure the presence of immunologically naïve, susceptible people.
Influenza B virus undergoes only minor antigenic changes.
In addition to compromising the mucociliary defenses of the respiratory tract, influenza infection promotes bacterial adhesion to the epithelial cells. Pneumonia may result from a viral pathogenesis or from a secondary bacterial infection. Influenza may also cause a transient or low-level viremia but rarely involves tissues other than the lung.Influenza infection leads to an inflammatory cell response of the mucosal membrane, which consists primarily of monocytes and lymphocytes and few neutrophils. Submucosal edema is present. Lung tissue may reveal hyaline membrane disease, alveolar emphysema, and necrosis of the alveolar walls (Figure 57-3).Interferon and cytokine responses, which peak at almost the same time as virus in nasal washes, may be sufficient to control the infection, and are responsible for the systemic "flulike" symptoms. T-cell responses are important for effecting recovery and immunopathogenesis, but antibody, including vaccine-induced antibody, can prevent disease. As for measles, influenza infection depresses macrophage and T-cell function, hindering immune resolution. Of interest, recovery often precedes detection of antibody in serum or secretions.Protection against reinfection is primarily associated with the development of antibodies to HA, but antibodies to NA are also protective. The antibody response is specific for each strain of influenza, but the cell-mediated immune response is more general and is capable of reacting to influenza strains of the same type (influenza A or B virus). Antigenic targets for T-cell responses include peptides from HA but also from the nucleocapsid proteins (NP, PB2) and M1 protein. The NP, PB2, and M1 proteins differ considerably for influenza A and B but minimally between strains of these viruses; hence T-cell memory may provide future protection against infection by different strains of either influenza A or B.
Protection against reinfection is primarily associated with the development of antibodies to HA, but antibodies to NA are also protective. The antibody response is specific for each strain of influenza, but the cell-mediated immune response is more general and is capable of reacting to influenza strains of the same type (influenza A or B virus). Antigenic targets for T-cell responses include peptides from HA but also from the nucleocapsid proteins (NP, PB2) and M1 protein. The NP, PB2, and M1 proteins differ considerably for influenza A and B but minimally between strains of these viruses; hence T-cell memory may provide future protection against infection by different strains of either influenza A or B.
