For centuries influenza epidemics have plagued man; with influenza probably being the disease described by Hippocrates in 412 BC. Today it remains a major cause of morbidity and mortality worldwide with large segments of the human population affected every year. Many animal species can be infected by influenza viruses, often with catastrophic consequences. An influenza pandemic is a continuing global level threat. The 1918 influenza pandemic is a modern example of how devastating such an event could be with an estimated 50 million deaths worldwide.
Influenza viruses belong to the family of Orthomyxoviridae; viruses with segmented RNA genomes that are negative sense and single-stranded (Baltimore 1971). Influenza virus strains are named according to their type (A, B, or C), the species from which the virus was isolated (omitted if human), location of isolate, the number of the isolate, the year of isolation, and in the case of influenza A viruses, the hemagglutinin (H) and neuraminidase (N) subtype. For example, the virus of H5N1 subtype isolated from chickens in Hong Kong in 1997 is: influenza A/chicken/Hong Kong/220/97(H5N1) virus. Currently 16 different hemagglutinin (H1 to H16) subtypes and 9 different neuraminidase (N1 to N9) subtypes are known for influenza A viruses. Most human disease is due to influenza viruses of the A type. The events of influenza infection have been annotated in Reactome primarily use protein and genome references to the Influenza A virus A/Puerto Rico/8/1934 H1N1 strain.
The influenza virus particle initially associates with a human host cell by binding to sialic acid receptors on the host cell surface. Sialic acids are found on many vertebrate cells and numerous viruses make use of this ubiquitous receptor. The bound virus is endocytosed by one of four distinct mechanisms. Once endocytosed the low endosomal pH sets in motion a number of steps that lead to viral membrane fusion mediated by the viral hemagglutinin (HA) protein, and the eventual release of the uncoated viral ribonucleoprotein complex into the cytosol of the host cell. The ribonucleoprotein complex is transported through the nuclear pore into the nucleus. Once in the nucleus, the incoming negative-sense viral RNA (vRNA) is transcribed into messenger RNA (mRNA) by a primer-dependent mechanism. Replication occurs via a two step process. A full-length complementary RNA (cRNA), a positive-sense copy of the vRNA, is first made and this in turn is used as a template to produce more vRNA. The viral proteins are expressed and processed and eventually assemble with vRNAs at what will become the budding sites on the host cell membrane. The viral protein and ribonucleoprotein complexes are assembled into complete viral particles and bud from the host cell, enveloped in the host cell's membrane.
Infection of a human host cell with influenza virus triggers an array of defensive host processes. This coevolution has driven the development of host processes that interfere with viral replication, notably the production of type I interferon. At the some time the virus counters these responses with the viral NS1 protein playing a central role in the viral response to the host cells defense.
