Orthomyxoviridae
The Orthomyxoviridae (influenza viruses) are a major determinant
of morbidity and mortality caused by respiratory disease, and outbreaks
of infection sometimes occur in worldwide epidemics. Influenza has been
responsible for millions of deaths worldwide. Mutability and high
frequency of genetic reassortment and antigenic changes in the viral
surface glycoproteins make influenza viruses formidable challenges for
control efforts.
The Orthomyxoviridae (orthos, Greek for "straight"; myxa, Greek for
"mucus") are a family of RNA viruses that includes five genera:
Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus and
Thogotovirus. .The first three genera contain viruses that cause influenza
in vertebrates, including birds, humans, and other mammals. Isaviruses
infect salmon; thogotoviruses infect vertebrates and invertebrates, such as
mosquitoes and sea lice.
Properties of Orthomyxoviruses
Important properties of Influenza viruses are summarized as
following in table (1):
Table (1): Important properties of Influenza viruses
Virion: Spherical, pleomorphic, 80–120 nm in diameter (helical
nucleocapsid, 9 nm)
Composition: RNA (1%), protein (73%), lipid (20%), carbohydrate
(6%)
Genome: Single-stranded RNA, segmented (eight molecules), negativesense, 13.6 kb overall size
Proteins: Nine structural proteins, one nonstructural
Envelope: Contains viral hemagglutinin (HA) and neuraminidase (NA)
proteins
Replication: Nuclear transcription; capped 5' terminal of cellular RNA
scavenged as primers; particles mature by budding from plasma
membrane
Outstanding characteristics:
Genetic reassortment common among members of the same genus
Influenza viruses cause worldwide epidemics
Classification
In a phylogenetic-based taxonomy the "RNA viruses" includes the
"negative-sense ssRNA viruses" which includes the Order
"Mononegavirales", and the Family "Orthomyxoviridae" . The generaassociated species and serotypes of Orthomyxoviridae are shown in the
following table.
Table (2): Orthomyxoviridae Genera, Species, and Serotypes
Species (* indicates
Genus
type species)
Influenzavirus
Influenza A virus*
A
Serotypes or
Subtypes
H1N1, H1N2,
H2N2, H3N1,
H3N2, H3N8,
H5N1, H5N2,
H5N3, H5N8,
H5N9, H7N1,
H7N2, H7N3,
H7N4, H7N7,
H9N2, H10N7
Influenzavirus
Influenza B virus*
B
Influenzavirus
Influenza C virus*
C
Infectious salmon
Isavirus
anemia virus*
Thogoto virus*
Thogotovirus
Dhori virus
Quaranfil virus,
Johnston Atoll virus,
Lake Chad virus
Hosts
Human, pig,
bird, horse
Human, seal
Human, pig
Batken virus, Dhori
virus
Atlantic
salmon
Tick,
mosquito,
mammal
(including
human)
Influenza A
Influenza A viruses are further classified, based on the viral surface
proteins hemagglutinin (HA or H) and neuraminidase (NA or N)...
Sixteen H subtypes (or serotypes) and nine N subtypes of influenza A
virus have been identified.
Figure (1) Diagram of influenza nomenclature.
Further variation exists; thus, specific influenza strain isolates are
identified by a standard nomenclature specifying virus type, geographical
location where first isolated, sequential number of isolation, year of
isolation, and HA and NA subtype.
Examples of the nomenclature are:
1. A/Brazliane/59/2007 (H1N1)
2. A/Moscow/10/99 (H3N2)
The type A viruses are the most virulent human pathogens among the
three influenza types and causes the most severe disease. The serotypes
that have been confirmed in humans, ordered by the number of known
human pandemic deaths, are:

H1N1 caused "Spanish Flu" in 1918, "Swine flu" in 2009.






H2N2 caused "Asian Flu".
H3N2 caused "Hong Kong Flu".
H5N1 is a pandemic threat.
H7N7 has unusual zoonotic potential
H1N2 is endemic in humans and pigs.
H9N2, H7N2, H7N3, H10N7.
Influenza B
Influenza B virus is almost exclusively a human pathogen, and is less
common than influenza A. The only other animal known to be susceptible
to influenza B infection is the seal. This type of influenza mutates at a
rate 2-3 times lower 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.
Influenza C
The influenza C virus infects humans and pigs, and can cause severe
illness and local epidemics. However, influenza C is less common than
the other types and usually seems to cause mild disease in children.
Structure & Function of Hemagglutinin
The HA protein of influenza virus binds virus particles to susceptible
cells and is the major antigen against which neutralizing (protective)
antibodies are directed. Variability in HA is primarily responsible for the
continual evolution of new strains and subsequent influenza epidemics.
Hemagglutinin derives its name from its ability to agglutinate
erythrocytes under certain conditions.
The amino acid sequence for HA can be calculated from the sequence
of the HA gene, and the three-dimensional structure of the protein has
been revealed by x-ray crystallography, so it is possible to correlate
functions of the HA molecule with its structure.
The primary sequence of HA contains 566 amino acids A short signal
sequence at the amino terminal inserts the polypeptide into the
endoplasmic reticulum; the signal is then removed. The HA protein is
cleaved into two subunits, HA1 and HA2, that remain tightly associated
by a disulfide bridge. A hydrophobic stretch near the carboxyl terminal of
HA2 anchors the HA molecule in the membrane, with a short hydrophilic
tail extending into the cytoplasm. Oligosaccharide residues are added at
several sites.
Structure & Function of Neuraminidase
The antigenicity of NA, the other glycoprotein on the surface of
influenza virus particles, is also important in determining the subtype of
influenza virus isolates.
The spike on the virus particle is a tetramer, composed of four
identical monomers . A slender stalk is topped with a box-shaped head.
There is a catalytic site for NA on the top of each head, so that each NA
spike contains four active sites.
The NA functions at the end of the viral replication cycle. It is a
sialidase enzyme that removes sialic acid from glycoconjugates. It
facilitates release of virus particles from infected cell surfaces during the
budding process and helps prevent self-aggregation of virions by
removing sialic acid residues from viral glycoproteins. It is possible that
NA helps the virus negotiate through the mucin layer in the respiratory
tract to reach the target epithelial cells
Life cycle of influenza virus
Typically, influenza is transmitted from infected mammals through
the air by coughs or sneezes, creating aerosols containing the virus, and
from infected birds through their droppings. Influenza can also be
transmitted by saliva, nasal secretions, feces and blood. Infections occur
through contact with these bodily fluids or with contaminated surfaces.
Flu viruses can remain infectious for about one week at human body
temperature, over 30 days at 0 °C (32 °F), and indefinitely at very low
temperatures (such as lakes in northeast Siberia). They can be inactivated
easily by disinfectants and detergents. The viruses bind to a cell through
interactions between its hemagglutinin glycoprotein and sialic acid sugars
on the surfaces of epithelial cells in the lung and throat. The cell imports
the virus by endocytosis. In the acidic endosome, part of the
haemagglutinin protein fuses the viral envelope with the vacuole's
membrane, releasing the viral RNA (vRNA) molecules, accessory
proteins and RNA-dependent RNA polymerase into the cytoplasm. These
proteins and vRNA form a complex that is transported into the cell
nucleus, where the RNA-dependent RNA transcriptase begins
transcribing complementary positive-sense cRNA. The cRNA is either
exported into the cytoplasm and translated 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) or transported back into the nucleus to bind vRNA and
form new viral genome particles . 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, RNAdependent RNA transcriptase, 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. 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. After the release of new influenza virus, the host cell
dies.
The separation of the genome into eight separate segments of vRNA
allows mixing (reassortment) of the genes if more than one variety of
influenza virus has infected the same cell (superinfection). The resulting
alteration in the genome segments packaged in to viral progeny confers
new behavior, sometimes the ability to infect new host species or to
overcome protective immunity of host populations to its old genome
(antigenic shift is a property of influenza virus and results in the sudden
appearance of a serotypec which has a potential to cause a pandemic
( major antigenic changes in HA or NA ).while the antigenic drift that
occurs within a serotype such as H1N1 resulted in appearance of aviriant
with minor antigenic differences from parent strain is due to the
accumulation of point mutations in the gene resulting in amino acid
changes in the protein )
Clinical Findings
Uncomplicated Influenza , Pneumonia , Reye's Syndrome
Serology
Antibodies to several viral proteins (hemagglutinin, neuraminidase,
nucleoprotein, and matrix) are produced during infection with influenza
virus. The immune response against the HA glycoprotein is associated
with resistance to infection.
Treatment
Amantadine hydrochloride & Remantadine are M2 ion channel
inhibitors for systemic use for treatment of influenza A . The NA
inhibitors zanamivir & oseltamivir were used for treatment of influenza A
& B.