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Influenza is an infectious diseases caused by influenza virus that cause seasonal epidemics of respiratory infection. This infection sometimes can be life threatening. Influenza circle the universe every year and the virus changes slowly once it spreads due to mistakes created while it copying its genetic material. Because of these changes, our immune system face difficulties to recognize the second time of influenza infection. This explain why previous influenza infection does not prevent following infections(1).
Influenza virus obtains its name from the Latin word 'influentia' which means 'influence'. Influenza viruses have been divided into three types,(A, B and C) and this based on their nucleoprotein antigen variation.
Type A influenza viruses are exposed to slow mutations (antigenic drift) and abrupt changes in their surface protein (antigenic shift). They can cause major pandemics due to their variability.
Type B inluenza viruses , endure antigenic drift only and this cause localized epidemics.
Type C influenza viruses cause sporadic diseases as they are stable antigenically.
Influenza A viruses tend to get the majority of the attention. It is the most common and the scariest one between the three types of influenzas, causing the most serious epidemics in history. Influenza A viruses infect human as well as a wide range of avian and mammalian species (2).
Influenza A virus Classification:
Influenza A virus classified within the genus Orthomyxovirus of Orthomyxoviridae family .Influenza A viruses are further classified according to their viral surface proteins hemagglutinin (HA or H) and neuraminidase (NA or N). There are sixteen H subtypes or serotypes have been identified and nine N subtypes in animals whereas in the human 1-3 of HA subtypes and 1-2 NA subtypes are exist. Additional variation exist; therefore particular influenza strain isolates are remain recognized via a regular nomenclature identifying virus type, geographic site where initial isolated, serial number, time of isolation and HA and NA subtype (3).
Examples of the nomenclature are:
Figure 1: shows a diagram of the influenza virus nomenclature(4)
Table 1 shows the serotypes that have been identified in humans and sequenced by the number of known human pandemic deaths (5):
Influenza A subtype
Caused "Spanish Flu" in 918
and "swine flu " in 2009
Caused "Asian flu"
Caused "Hong Kong Flu"
Is a pandemic threat
Has unusual zonootic potentia
Is endemic in humans and pigs
Influenza A virus structure:
The influenza A virion is roughly spherical with a diameter of 80-120 nm. It is an enveloped virus. The outer layer of the virus is a lipid membrane that is acquired from the host cell as the virus replicates inside it. Placed into the lipid membrane are 'spikes' which are glycoproteins as they contain proteins connected to sugar, which known as hemagglutinin (HA) and neuraminidase (NA). These both are the proteins which confirm the influenza virus subtypes, for example(A / H1N1). Furthermore, HA and NA are essential in the immune reaction against the viruses. The neuraminidase protein is the target of antiviral drugs (Relenza & Tamiflu). On the other hand, the M2 protein which included in the lipid membrane is the target of the antiviral adamantanes (amantadine & rimantadine) (6).
The viral protein M1 or the matrix protein is under the lipid membrane, which forms a shell and gives the lipid envelope strength and inflexibility. Viral RNAs are located within the interior of the virionm, which contains 8 negative- sense RNA segments. They are the virus genetic material. Each one of the RNA segment consists of RNA linked with numerous proteins, which are B1,B2,PA,NP. These RNA segments are the influenza virus genous. NEP protein also included in the interior of the influenza virion.
Figure 2: shows the structure of influenza A virus (6).
Pathogenesis of influenza a virus:
Once the virus of influenza get into the respiratory track via aerosol, contact with saliva or any other respiratory secretion from an infected individual, it binds and replicates within the epithelial cells. The influenza virus replicates in upper and lower respiratory track cells. The respiratory track become heavily damaged due to combination between viral replication and the immune system reaction that may cause loss of the cells that are lining the respiratory tract, as infection settles the epithelium in the respiratory track is regenerated and that process may acquire up to month (6).
Replication of influenza A virus:
The influenza A virus replicates within a host cell that it infects and use the resources of the infected cell to generate hundreds of copies of the viral RNA. The replication of the influenza A viruses involves such steps in order to release to other cells and infect it and they are (7):
The influenza A virus attaches to the host cell and bind its hemagglutinin to the sialic acid that found on glycoproteins receptors of the host cell.
Then the cell endocytoses the virus.
The virus release its nucleocapsid into the cytoplasm of the host. Then the virus modifys shape and combines its envelope with the endosomal membrane within the acidic surroundings of the endosome.
After that, the nucleocapsid moves to the host nucleus.
The virus performs primary transcription within the host nucleus to produce essential proteins for replications. In influenza A, 10 proteins consequence the translation of the 8 segments of the genome, as well as HA, PB1,PB2, nucleoprotein, another RNA polymerase compound, 2 matrix proteins and 2 NS proteins.
Then the 8 complementary positive sense RNA strands are made from the negative sense RNA segments, which exit the nucleus by the help of various proteins into the host cell cytoplasm.
In the meanwhile, the HA and NA undergo glycogation, polymerization and acylation in the cytoplasm .
The HA, NA and M2 all together move to the plasma membrane and meet M1 to start budding process. At least 8 RNA segments move towards the site and the influenza virus buds.
Finally the NA destroys the receptors of sialic acid on the membrane, consequently permitting the virus to leave the cell.
Figure 3: shows the replication process in influenza A virus(8).
Influenza A is known to cause an acute infection of the host and starts immune reactions that activate most parts of the immune defense system. Mainly, the primary innate response are responsible for the acute symptoms, including cytokine release (IFNÎ±/Î²), invasion of neutrophils or natural killer cells. Cell activation Innate immunity is important for the adaptive immune response, as it limits the viral replication and antigens load. Moreover, during contact with viruses the co-stimulatory molecules that are stimulated on the cells of the innate immune system are activated by antigen-specific lymphocytes of the adaptive immune (Figure 3). Influenza A infection stimulates both humoral immunity, as well as cellular immunity (cytotoxic T cell responses) (8).
Humoral immunity: Influenza A infection results in the systemic production of antibody to influenza glycoproteins Hemagglutinin and Neuraminidase, besides M and NP proteins. For example, Hemagglutinin-specific immunoglobulins (IgM, IgA and IgG) appear in 2 weeks of virus inoculation(9).
Cellular immunity: CD4 T lymphocytes help B lymphocytes to produce anti-H and anti-N antibodies (Figure 3). CD4 T helper cells recognize the epitopes in H and T helper cells promote the production of virus-specific CD8 cytotoxic T lymphocytes (10).
Figure 4. The humoral and cell-mediated immune response to influenza virus infection (11). The humoral branch of the immune system comprises B-lymphocytes (left), which after interaction with influenza differentiate into antibody-secreting plasma cells. The cellular response (right) starts with antigen presentation via MHC I (black) and II (blue) molecules by dendritic cells, which then leads to activation, proliferation and differentiation of antigen-specific T cells (CD4 or CD8). These cells gain effector cell function to either help directly, release cytokines, or mediate cytotoxicity following recognition of antigen (Adapted from Flint 2004). Not shown is the formation of a cellular memory immune response and the various forms of innate immunity induced by influenza.
The influenza virus can be transmitted between humans by three ways(6):
Direct contact with infected secretions from infected individuals.
Direct contact with contaminated objects such as doorknobs and toys.
By inhalation of viruses-laden aerosols.
Influenza is mainly spread from person to person through the air. And virus particles are released into the air through sneezing and coughing of persons who are infected with influenza. Crowded conditions in enclosed spaces provide ideal conditions for the spread of influenza.
Influenza A is the most significant emerging and re-emerging infectious disease. For centuries, it has been the major cause of epidemics and pandemics worldwide. An epidemic arise each( 2-3) years with surplus mortality. Recently, influenza epidemics predispose to occur every winter. Pandemic means the number of worldwide epidemics incidence(12).
The influenza A outbreaks are known to happen in two patterns:
pandemics (30 - 40) years, with high more mortality
epidemics that more commonly, with minor surplus mortality and usually mild isolated outbreaks.
Latest flu pandemics(13)
Name of pandemic
Asiatic (Russian) Flu
1.5 to 2Â million
Hong Kong Flu
As of 25 June 2010
Hemagglutinin and neuraminidase regularly change, in fact developing in response to antibodies occurring in immune or partially immune populations. Consequently infection is pursued by antibodies, which cause mutations that let the virus survive. At irregular period of (10-40 ) years, viruses emerge that show many antigenic differences from common subtypes. Thus, the population have no defensive antibodies against the newest antigens, they cause in all different age groups pandemic disease (14).
It occurs when gene segments from two different viruses get mixed and repackaged into the same virion.Â This is likely whenÂ two different viruses infect the same cell at the same time(15).
Figure 5: demonstrate the reassortment in influenza A (18).
It is amajor, sudden change in the influenza A viruses in both or one surface antigens HA or NA that arise at varying periods. It is a specific type of reassortment where HA or NAÂ gene segmentsÂ from two different strains are switched. This usually occurs when an avian strain and human strain infect the same pig cell. Such a "shift" occurred 2009, when a new H1N1 virus (swine flu) with a new gene combination appeared to infect people and spread rapidly, causing a pandemic(16).
Figure 6: shows antigenic shift (19).
Antigenic Drift: means minor changes in the virus's surface antigens that occur constantly over time. It generates new virus strains that may not be recognized by the body's immune system. This mechanism occurs as follows: a person infected with a specific influenza virus strain developing antibodies against that virus. As newer virus strains emerge, the antibodies against the older strains no longer recognize the newer virus, and reinfection can occur. This is the reason why people can get influenza more than once. Antigenic drift may result in an epidemic because the protection that remains from past exposures to similar viruses is incomplete (17).
Figure 7: shows antigenic drift in influenza (20).
The characteristic symptoms of influenza infection appear after the incubation phase of 48 hours. It is similar to the common cold, but more severe (table 3)
Characteristic high (39-40 oC) 3-4 days
General aches and pains
Usual often sever
Fatigue and weakness
Can last for 2-3 weeks
Early and prominent
chest discomfort cough
Common can be dry and severe
Mild to moderate; hacking cough
Malaise, myalgia, dry tickling throat, dirrhoea and photophobia.
Table3 shows the difference between influenza symptoms and those of a common cold(21).
Complications of the influenza A infection can include dehydration, bacterial pneumonia, sinus infection, ear infections, and worsening of chronic medical conditions, such as congestive heart failure, asthma, or diabetes(21).
During epidemics, the diagnosis of the influenza can be achieved on the basis of the clinical symptoms. Isolated cases of suspected influenza should be investigated for these may represent the first cases of an impending epidemic (22).
Rapid Diagnosis - by collecting nasopharyngeal aspirates specimen as it is more sensitive. Though, nasal and throat swabs are more usually used.
Indirect immunofluorescence. Cells from the pathological specimens can be examined to check the presence of influenza A virus.
EIA tests( Enzyme Immuno Assay) to detect influenza A viral antigens.
RT-PCR(Reverse Transcription Polymerase Chain Reaction) assays to detect influenza RNA. The product of PCR could be sequenced for epidemiological investigation and strain identification.
Virus Isolation - Throat swabs, nasal washings and NPA can be use for virus isolation. The specimen is inoculated in tissue culture or embryonated eggs. Then the isolated viruses could be identified by using serological or molecular methods. Further classification of influenza isolates into subtypes and strains is extremely specific responsibility of the WHO reference laboratories. Identification of HA type is preformed by HAI tests and also the NA type is identified.
Serology - As the virus cannot be isolated from all suspected cases of infection, the diagnosis is done by demonstrating the rise of serum antibody towards the infecting virus.
Nasopharyngeal swab/aspirate, nasal swab/aspirate/wash, throat swab, bronchioalveolar lavage
Immunofluorescence [Direct Fluorescent Antibody (DFA) or Indirect Fluorescent Antibody (IFA) Staining]
Nasopharyngeal swab/aspirate, nasal swab/aspirate/wash, throat swab,
RT-PCR (Reverse transcription polymerase chain reaction.
Nasopharyngeal swab/aspirate, nasal swab/aspirate/wash, throat swab, bronchioalveolar lavage sputum
paired acute and convalescent serum samples6
2 weeks or more
Enzyme Immuno Assay (EIA)
Nasopharyngeal swab/aspirate, nasal swab/aspirate/wash, throat swab,
2 weeks or more
Direct influenza diagnostic tests. For example: SASâ„¢ FluAlert A4,8
Currently , treatment of influenza A is completely symptomatic. Anti-viral treatment started after 48 hours of symptoms start. It can reduce illness severity and shorten the duration of fever and symptoms. There are two classes of antiviral available for influenza A treatmentwhich are:
Amantidine/Rimantdine, which inhibit the uncoating viral RNA in the host cells and prevent virus replication.
Zanamivir/ Oseltamvir(Tamiflu and Relenza) which act as Neuraminidase inhibitors.
Neuraminidase inhibitors, in specific Amantidine has been replaced by Oseltamivir as the choice of anti-viral drug for influenza infections treatment. Zanamivir can cause bronchospasm so it is not recommended for patient with asthma or chronic obstructive lung disease(23).
*GI=gastrointestinal , CNS= central nerve system
Table 5: (23)
The best way to prevent influenza is by getting the influenza vaccine or the flu shot. The influenza vaccine must include HA and NA antigens to stimulate the creation of neutralizing antibody, local IgA antibody and cellular immunity. Influenza A virus usually is spread through the air so practicing good hygiene, covering mouth while coughing and washing hands frequently may help to avoid getting influenza or spreading it to others(24).
Types of vaccine:
The WHO monitors the influenza viruses throught the world and recommends which strains are to be included in the current year's vaccine.There are two types of the influenza vaccines(25):
Shot (TIV-Trivalent inactivated vaccine). All currently available vaccines are grown in emborynic hen's eggs and then chemically inactivated and purified. It can be whole virus vaccine, split virus vaccine or subunit vaccine (table 6) (26).
Table 6: (26)
Â Â Inhaler/Nasal spray (LAIV-Live, attenuated influenza vaccine) (table 7).
Conclusion and future outlook:
Influenza virus infection directs to acute development of respiratory disease. There have been many achievements in the development of influenza vaccines and antiviral medications to prevent and treat influenza.Technological improvement, comprising genetic and useful studies, will facilitate to gain a deeper insight into the pathogenesis of historic and currently circulating virulent influenza strains. This knowledge and an advanced understanding on the viral immune defence mechanisms in the human lung will hopefully facilitate the development of better treatment options and more effective vaccines to be distributed worldwide against present and future influenza virus variants.