Influenza-A Virus Replication Cycle
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Influenza-A Virus Replication Cycle
Influenza, commonly called "the flu", is an infection of the respiratory tract caused by the Influenza virus. Compared with most other viral respiratory infections, such as the common cold, Influenza infection often causes a more severe illness. Typical Influenza illness includes fever and respiratory symptoms, such as cough, sore throat, runny or stuffy nose, as well as headache, muscle aches, and often extreme fatigue. Although nausea, vomiting, and diarrhea can sometimes accompany Influenza infection, especially in children, these symptoms are rarely the primary symptoms. Most people who get the flu recover completely in 1 to 2 weeks, but some people develop serious and potentially life-threatening medical complications, such as pneumonia. In an average year, Influenza is associated with more than 20,000 deaths nationwide and more than 100,000 hospitalizations. Flu-related complications can occur at any age; however, the elderly and people with chronic health problems are much more likely to develop serious complications after Influenza infection than are younger, healthier people (Ref.1).

There are three types of Influenza virus: A, B and C, of which Influenza-A virus is both the best characterized and the most serious threat to public health. Influenza Types-A and B are responsible for epidemics of respiratory illness that occur almost every winter and are often associated with increased rates for hospitalization and death. Influenza Type-C infection usually causes either a very mild respiratory illness or no symptoms at all; it does not cause epidemics and does not have the severe public health impact that Influenza Types-A and B do (Ref.1). In humans, Influenza viruses are normally confined to the upper respiratory tract; however, Influenza viruses can invade a patient’s lower respiratory tract if it is colonized by bacteria (e.g. in patients suffering from chronic bronchitis or emphysema). Influenza-A virus infects a variety of animals, including humans and birds. Although the natural reservoir for all known subtypes of Influenza-A (Hemagglutinins H1 through H15 and Neuraminidases N1 through N9) is wild waterfowl, only three subtypes are currently circulating among humans (H1N1, H1N2, and H3N2). However, during the past few years, several subtypes of avian Influenza-A have been shown to cross the species barrier and infect humans. During an outbreak of a highly pathogenic Influenza-A (H5N1) virus among poultry in Hong Kong in 1997, 6 of 18 people with confirmed infection died. Avian Influenza-A (H9N2) viruses were also isolated from children in Hong Kong in 1999, but this infection resulted in only mild, self-limiting illnesses (Ref.2).

Influenza viruses are one of the few RNA viruses to undergo replication and transcription in the nucleus of their host cells. Virus replication begins with entry of the virus into the host cell by a process of engulfment called viropexis or receptor-mediated endocytosis. Influenza-A virus HA binds to a Sialic acid receptor on the surface membrane of the infected cell and is then endocytosed. While in the acidic endosome, the HA protein undergoes a conformational change to its low pH form that exposes a hydrophobic fusion peptide. Following internalization, the calthrin coat is removed and vesicles fuse with the endosomes. The virus is exposed to the cytoplasm and the vRNPs (viral Ribonucleoprotein Complex) are released and then transported into the nucleus (Ref.3). In the nucleus, the vRNPs serve as templates for the production of two forms of positive-sense RNA: viral mRNA (messenger RNA) and cRNA (complementary RNA). The synthesis of mRNA is catalyzed by the viral RNA-dependent RNA polymerase (comprising the three subunits PA, PB1 and PB2), which is part of the incoming vRNP complex. Viral mRNAs are processed in an analogous fashion to other eukaryotic mRNAs; that is, they are capped (i.e. contain a methylated 5 guanosine residue) and are polyadenylated (i.e. contain a sequence of polyadenylic acid at their 3 end), and exported from the nucleus for translation by cytoplasmic ribosomes. The nuclear export of viral mRNA utilizes the ‘machinery’ of the host cell, but is selective; export is controlled by the viral non-structural protein NS1 (Ref.4). Many viral proteins (NP, M1, NS2 and the polymerases) are then imported into the nucleus for the final stages of replication and for vRNP assembly. The viral cRNA is neither capped nor polyadenylated, but, instead, is a perfect copy of the template. These cRNAs then form the template for synthesis of further negative-sense genomic vRNA segments for amplification of mRNA synthesis and packaging into progeny virions. Both cRNA and vRNA molecules contain a 5’ triphosphate group. Progeny virions are assembled at the apical surface of the plasma membrane and, therefore, newly synthesized RNPs must be exported from the nucleus and directed to the plasma membrane to allow their incorporation into budding virions (Ref.3).

Major outbreaks of Influenza are associated with Influenza virus Type A or B. Infection with Type B Influenza is usually milder than Type A. Type C virus is associated with minor symptoms. The virus is spread from person to person via small particle aerosols (less than 10µm) which can get into respiratory tract. The incubation period is short, about 18 to 72 hours. Virus concentration in nasal and tracheal secretions remains high for 24 to 48 hours after symptoms start and may last longer in children. Titers are usually high and so there are enough infectious particles in a small droplet to start a new infection. The disease is usually most severe in very young children and the elderly. Children may have no antibodies and the small diameter of components of the respiratory tract in the very young also means that inflammation and swelling can lead to blockage of parts of respiratory tract, sinus system or Eustachian tubes. In the elderly, Influenza is often severe because they often have an underlying decreased effectiveness of the immune system and/or chronic obstructive pulmonary disease or chronic cardiac disease. A humoral antibody response is the main source of protection. IgG and IgA are important in protection against reinfection. Antibody to the HA protein is most important since this can neutralize the virus and prevent the virus initiating the infection. Antibody to the NA protein has some protective effect since it seems to slow the spread of the virus (Ref.5).