Influenza virus is an infectious agent belonging to the virus family Orthomyxoviridae that causes a respiratory tract infection (influenza or 'flu') in vertebrates. There are three main species, and of these, influenza A viruses cause the most virulent infections in humans and are also a common cause of zoonotic infections.
Influenza virus is a member of the orthomyxoviridae family and is divided into three virus types A, B and C based on differences in expression of the internal proteins NP and matrix protein (M1). Influenza viruses B and C are not classified by subtype, however influenza virus A is further classified by strains. The influenza virus A genome is comprised of 8 RNA segments that code for 11 different proteins, two of which are the two cell surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). Influenza virus A is divided into subtypes based on the expression and antigenic differences of these two proteins. And Influenza virus is negative sense single-stranded segmented RNA viruse. RNA segment is encapsidated by a protective nucleoprotein (NP) to form a nucleocapsid or a ribonucleoprotein NP (RNP) complex, which are transcriptionally active.
The virus uses both endocytosis and fusion for entry into host cells during infection. In humans, influenza can infect any cells that express the α-2,6-linked sialic acid residues, including nasal mucosal, tonsil, trachea and lung cells, and can be contracted via airborne, droplet, or contact transmission. Following the interaction between the influenza viral HA protein and α-2,6-linked sialic acid residues, the bound virus is taken up into the cell via receptor-mediated endocytosis. The low pH of the virus containing endosome causes a change in HA conformation, which promotes fusion with the endosomal membrane and the release of the viral genome-containing nucleocapsid into the cytosol.
After the nucleocapsid is released into the cytoplasm, it is transported into the nucleus of the host cell, where replication and transcription occur. Within the nucleus, viral RNA polymerases associate with the negative sense single-stranded viral RNA, which is transcribed to make complementary positive sense RNA. In addition to the replication of the viral genome, the influenza virus also promotes the transcription and translation of HA and NA proteins, both of which localize to the host cell plasma membrane and consequently the viral envelope, in addition to M1, matrix protein, and M2, an ion channel protein. Since the influenza virus assembles and buds from the plasma membrane, all the viral components synthesized within the host cells must be directed to the apical domain of the plasma membrane. Both HA and NA possess the biochemical determinants in their structures that target them to the apical plasma membrane. HA and NA proteins are synthesized in the same compartment of membrane-bound polyribosomes and are transported together from the endoplasmic reticulum through the Golgi network to the plasma membrane, while M1 and M2 are synthesized on free cytosolic polyribosomes and then move to the plasma membrane. As the infection progresses, more and more viral proteins accumulate on the plasma membrane indicating that the release of influenza virus progeny from the host cell is imminent.
In the later part of the infection cycle, the viral RNA genome, polymerase subunits, and nucleoprotein will form RNP complexes, which will then be exported from the nucleus to the cell membrane to form new virions, which will exit the host cell via budding, enveloped in a lipid coating obtained from the host cell plasma membrane. RNP complexes congregate near the areas of the plasma membrane with the highest concentrations of the influenza virus proteins HA, NA, M1, and M2. The exportation process is initiated by viral activation of the intracellular mitogen-activated protein kinase (MAPK) signaling cascade. Evidence suggests that it is the accumulation of HA in the plasma membrane that actually triggers the activation of the MAPK signaling pathway via protein kinase C activation, resulting in RNP complex export from the nucleus. Virus bud formation is a complex process that involves membrane bending at the budding site, which is facilitated in part by the increased viscosity and asymmetry of the lipid bilayer in the areas of the plasma membrane with the highest concentrations of influenza virus proteins. After the opposing membranes of the virus bud fuse, the virus particle will separate from the host plasma membrane and be released into the extracellular environment.
Phipps-Yonas, Hannah Carrie. Analysis of the effect of type I interferon on the response of human DC subsets to influenza virus. Mount Sinai School of Medicine of New York University, 2009.
Paich, Heather A. The effects of adiposity and type II diabetes on the immune response to influenza virus in adults. The University of North Carolina at Chapel Hill, 2013.