Pandemic Influenza Transmission

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Palese P, Shaw ML. Orthomyxoviridae: the viruses and their replication. In: Knipe DM, Howley PM, Griffin DM, Lamb RA, Martin MA, eds. Fields Virology. 5th ed. Philadelphia: Lippincott, Williams, & Wilkins; 2006:1647-1689.
de Wit E, Fouchier RA. Emerging influenza. J Clin Virol. 2008;41:1-6. Abstract
World Health Organization (WHO). Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO. April 17, 2008. Available at: http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_04_17/en/index.html Accessed April 24, 2008.
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The Influenza Virus and Infection

Influenza A is an enveloped virus containing a segmented, negative-sense, single-stranded RNA genome. The envelope is derived by virus budding from infected cells and contains 2 major viral glycoproteins on the envelope surface: HA, which is responsible for receptor binding and virus fusion and entry, and NA, which is primarily involved in virus release.^[3]

The RNA genome and mRNAs are produced by a virally encoded RNA-dependent, RNA polymerase, which is very error-prone and lacks proofreading. This propensity for error during RNA transcription promotes constant mutation of the genome and thus the viral proteins, with mutations focusing on the surface glycoproteins HA and NA.^[2,3] The constant mutation of the surface antigens is termed antigenic drift and is the reason influenza vaccines must be formulated annually.

The segmented viral genome refers to the virus having multiple pieces or segments of RNA (8 to be exact) that encode the 11 viral proteins. This segmented genome enables reassortment: When 2 or more influenza viruses infect the same cells within a host, there is the potential for the different viruses to exchange or mix and match genomic segments, producing hybrid viruses. When this occurs and 1 or both of the surface proteins is changed, it is called antigenic shift.

Historically, antigenic shift has resulted in 2 of the 3 pandemics in the 20th century: the 1957 "Asian influenza," in which both the HA and NA and 1 internal segment were of avian origin, and the 1968 "Hong Kong influenza," in which the HA and 1 internal segment came from an avian influenza virus.^[2] Antigenic shift is not an absolute requirement for generation of a pandemic virus; however, as phylogenetic analyses of the genome from the 1918 "Spanish influenza" -- the most severe pandemic in recorded history -- have suggested, the virus was entirely avian in origin.^[2]

Influenza viruses initiate infection of host cells by HA binding to sialic acid residues attached to sugars on glycoproteins expressed on the surface of cells.^[3] This binding is generally restricted to sialic acids on the surface of respiratory or gastrointestinal epithelial cells. Although sialic acid is a ubiquitous molecule, influenza viruses from different host species (eg, human or avian) have different fine specificities that are based on the linkage of the sialic acid to the penultimate galactose sugar. Human influenza viruses preferentially bind to sialic acids linked by an alpha2,6 linkage, whereas avian influenza viruses preferentially bind to sialic acids linked by an alpha2,3 linkage.^[3]

Epithelial cells in the gastrointestinal tract of many avian species express an abundance of alpha2,3-linked sialic acids, and avian influenza viruses readily infect many of these species. In contrast, the upper respiratory tract of humans contains predominantly alpha2,6-linked sialic acids, allowing infection by human influenza viruses, but restricting binding of avian influenza viruses.^{[2,3, 6-10]} Upon HA binding, the virus is endocytosed by the cell; HA triggers fusion of the virus membrane with the endosome membrane; and the genomic segments are delivered to the cell along with the viral polymerase to initiate replication.