Orthomyxoviruses (Influenza Viruses):
- Influenza viruses are the only members of the orthomyxovirus family.Influenza
has been responsible for respiratory disease and millions of deaths. Also has
high frequency of genetic reassortment and result antigenic changes in the viral
surface glycoproteins. The term "myxo" in the Orthomyxoviruses refers to the
observation that these viruses interact with mucins (glycoproteins on the surface
of cells).
-Three immunologic types of influenza viruses are known, designated A, B, and
C. Antigenic changes continually occur within the type A group of influenza
viruses and to a lesser degree in the type B group, whereas type C appears to be
antigenically stable. Influenza A strains are also known for birds, chickens,
ducks, pigs, and horses. Some of the strains isolated from animals are
antigenically similar to strains circulating in the human population.
Virion: Spherical, 80–120 nm in diameter (helical nucleocapsid)
Genome: Single-stranded RNA, segmented (eight molecules)
Proteins: Nine structural proteins, one nonstructural
Envelope: Contains viral hemagglutinin (HA) and neuraminidase (NA)
proteins
Replication: Nuclear transcription; particles mature by budding from plasma
membrane
Other characteristics:
Genetic reassortment common among members of the same genus
Influenza viruses cause worldwide epidemics
Functions of Hemagglutinin & neuraminidase
*The function of the hemagglutinin is to bind to the cell surface receptor
(neuraminic acid, sialic acid) to initiate infection. In the clinical laboratory, the
hemagglutinin agglutinates red blood cells, which is the basis of a diagnostic test
called the hemagglutination inhibition test. The hemagglutinin is also the target
of neutralizing antibody.
*The neuraminidase cleaves neuraminic acid (sialic acid) to release progeny
virus from the infected cell. The hemagglutinin functions at the beginning of
infection, whereas the neuraminidase functions at the end. Neuraminidase also
degrades the protective layer of mucus in the respiratory tract. This enhances the
ability of the virus to infect the respiratory epithelium.
Classification & Nomenclature
-Genus Influenzavirus A contains human and animal strains of influenza type A;
Influenzavirus B contains human strains of type B; and Influenzavirus C contains
influenza type C viruses of humans and swine.
- Influenza viruses have both group-specific and type-specific antigens.
1. The internal ribonucleoprotein is the group-specific antigen that
distinguishes influenza A, B, and C viruses.
2. The hemagglutinin and the neuraminidase are the type-specific antigens
located on the surface. Antibody against the hemagglutinin neutralizes the
infectivity of the virus (and prevents disease), whereas antibody against the
group-specific antigen (which is located internally) does not. Antibody
against the neuraminidase does not neutralize infectivity but does reduce
disease, perhaps by decreasing the amount of virus released from the
infected cell and thus reducing spread.
-The standard nomenclature system for influenza virus isolates includes the
following information: type, host of origin, geographic origin, strain number, and
year of isolation. Antigenic descriptions of the HA and the NA are given in
parentheses for type A. The host of origin is not indicated for human isolates, eg,
A/Hong Kong/03/68(H3N2), but it is indicated for others, eg,
A/swine/Iowa/15/30(H1N1).
-So far, 16 types of HA (H1–H16) and nine types of NA (N1–N9), in many
different combinations, have been recovered from birds, animals, or humans.
Four HA (H1–H3, H5) and two NA (N1, N2) types have been recovered from
humans.
Antigenic Drift & Antigenic Shift
Influenza viruses are remarkable because of antigenic changes that occur in HA
and NA. Antigenic variants of influenza virus have a selective advantage over the
parental virus in the presence of antibody directed against the original strain. This
phenomenon is responsible for the unique epidemiologic features of influenza.
The two surface antigens of influenza undergo antigenic variation independent of
each other and result :
Antigenic Drifts, which are minor changes based on mutations in the genome
RNA . Antigenic drift is due to the accumulation of point mutations in the gene,
resulting in amino acid changes in the protein. Sequence changes can alter
antigenic sites on the molecule such that a virion can escape recognition by the
host's immune system. The immune system does not cause the antigenic
variation, but rather functions as a selection force that allows new antigenic
variants to expand. A variant must sustain two or more mutations before a new,
epidemiologically significant strain emerges.
Antigenic Shifts, which are major changes based on the reassortment of
segments of the genome RNA and Antigenic shift reflects drastic changes in the
sequence of a viral surface protein. The mechanism for shift is genetic
reassortment between human and avian influenza viruses.
-NOTE: Because influenza B virus is only a human virus, there is no animal
source of new RNA segments. Influenza B virus therefore does not undergo
antigenic shifts. It does, however, undergo enough antigenic drift that the current
strain must be included in the new version of the influenza vaccine produced
each year. Influenza B virus has no antigens in common with influenza A virus.
Summary of Replicative Cycle
1-The virus adsorbs to the cell when the viral hemagglutinin interacts with sialic
acid receptors on the cell surface.
2-The virus then enters the cell in vesicles and uncoats within an endosome.
uncoating is facilitated by the low pH within the endosome. This disrupts the
virion envelope and frees the nucleocapsid to enter the cytoplasm and then
migrate to the nucleus where the genome RNA is transcribed.
3-The virion RNA polymerase transcribes the eight genome segments into eight
mRNAs in the nucleus. Most of the mRNAs move to the cytoplasm, where they
are translated into viral proteins.
4- Some of the viral mRNAs remain in the nucleus, where they serve as the
template for the synthesis of the negative-strand RNA genomes for the progeny
virions.
5-The helical ribonucleoprotein assembles in the cytoplasm, matrix protein
mediates the interaction of the nucleocapsid with the envelope, and the virion is
released from the cell by budding from the outer cell membrane at the site where
the hemagglutinin and neuraminidase are located. The neuraminidase acts to
release the virus by cleaving neuraminic acid on the cell surface at the site of the
budding progeny virions.
Pathogenesis & Clinical Findings
After the virus has been inhaled, the neuraminidase degrades the protective
mucus layer, allowing the virus to gain access to the cells of the upper and lower
respiratory tract. The infection is limited primarily to this area and then viremia
rarely occurs.
Uncomplicated Influenza
Symptoms of classic influenza usually appear abruptly and include chills,
headache, and dry cough, followed closely by high fever, generalized muscular
aches. Respiratory symptoms typically last 3–4 days. The cough and weakness
may persist for 2–4 weeks after major symptoms.
Pneumonia
Serious complications usually occur only in the elderly and debilitated, especially
those with underlying chronic disease. Pregnancy appears to be a risk factor for
lethal pulmonary complications in some epidemics. The lethal impact of an
influenza epidemic is reflected in the excess deaths due to pneumonia and
cardiopulmonary diseases.
Pneumonia complicating influenza infections can be viral, secondary bacterial, or
a combination of the two. Increased mucous secretion helps carry agents into the
lower respiratory tract. Influenza infection enhances susceptibility of patients to
bacterial superinfection. This is attributed to loss of ciliary clearance, dysfunction
of phagocytic cells, and provision of a rich bacterial growth medium by the
alveolar exudate. Bacterial pathogens are most often Staphylococcus aureus,
Streptococcus pneumoniae, and H influenzae.
Reye's Syndrome
Reye's syndrome is an acute encephalopathy of children and adolescents, usually
between 2 and 16 years of age. The mortality rate is high (10–40%). The cause of
Reye's syndrome is unknown, but it is a recognized rare complication of
influenza B, influenza A, and herpesvirus varicella-zoster infections.