Orthomyxoviridae ()International Committee on Taxonomy of Viruses Index of Viruses — Orthomyxovirus (2006). In: ICTVdB—The Universal Virus Database, version 4. Büchen-Osmond, C (Ed), Columbia University, New York. is a family of negative-sense RNA viruses. It includes nine genera: Alphainfluenzavirus, Betainfluenzavirus, Gammainfluenzavirus, Deltainfluenzavirus, Isavirus, Mykissvirus, Quaranjavirus, Sardinovirus, and Thogotovirus. The first four genera contain viruses that cause influenza in birds (see also avian influenza) and mammals, including humans. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates (such as ticks and mosquitoes). The Quaranjaviruses are also arboviruses, infecting vertebrates (birds) and invertebrates (arthropods).
The four genera of Influenza virus that infect vertebrates, which are identified by antigenic differences in their nucleoprotein and matrix protein, are as follows: Alphainfluenzavirus infects humans, other mammals, and birds, and causes all flu pandemics Betainfluenzavirus infects humans and seals Gammainfluenzavirus infects humans and pigs Deltainfluenzavirus infects pigs and cattle.
Structure
The influenza virus virion is pleomorphic; the viral envelope can occur in spherical and filamentous forms. In general, the virus's morphology is ellipsoidal with particles 100–120 nm in diameter, or filamentous with particles 80–100 nm in diameter and up to 20 μm long. There are approximately 500 distinct spike-like surface projections in the envelope each projecting 10–14 nm from the surface with varying surface densities. The major glycoprotein (HA) spike is interposed irregularly by clusters of neuraminidase (NA) spikes, with a ratio of HA to NA of about 10 to 1.
The viral envelope composed of a lipid bilayer membrane in which the glycoprotein spikes are anchored encloses the nucleocapsids; nucleoproteins of different sizes; the arrangement within the virion is uncertain. The ribonuclear proteins are filamentous and fall in the range of 50–150 nm long with helical symmetry.
Genome
Viruses of the family Orthomyxoviridae contain six to eight segments of linear negative-sense single stranded RNA. They have a total genome length that is 10,000–14,600 nucleotides (nt). The influenza A genome, for instance, has eight pieces of segmented negative-sense RNA (13.5 kilobases total).
The best-characterised of the influenza virus proteins are hemagglutinin and neuraminidase, two large glycoproteins found on the outside of the viral particles. Hemagglutinin is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell. In contrast, neuraminidase is an enzyme involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. The hemagglutinin (H) and neuraminidase (N) proteins are key targets for antibodies and antiviral drugs, and they are used to classify the different serotypes of influenza A viruses, hence the H and N in H5N1.
The genome sequence has terminal repeated sequences, and these are repeated at both ends (i.e., at both the 5' end and the 3' end). These terminal repeats at the 5′-end are 12–13 nucleotides long. Nucleotide sequences at the 3′-terminus are identical, are the same in genera of the same family, most on RNA (segments), or on all RNA species. Terminal repeats at the 3′-end are 9–11 nucleotides long. Encapsidated nucleic acid is solely genomic. Each virion may contain defective interfering copies. In Influenza A (specifically, in H1N1) PB1-F2 is produced from an alternative reading frame in PB1. The M and NS genes produce two genes each (4 genes total) via alternative splicing.
Replication cycle
Typically, influenza is transmitted from infected mammals through the air by coughs or sneezes, creating aerosols containing the virus, and from infected birds through their droppings. Influenza can also be transmitted by saliva, nasal secretions, feces and blood. Infections occur through contact with these bodily fluids or with contaminated surfaces. On certain surfaces (i.e, outside of a host), flu viruses can remain infectious for about one week at human body temperature, over 30 days at , and indefinitely at very low temperatures (such as in lakes in northeast Siberia). They can be inactivated easily by disinfectants and detergents.
The virus's surface hemagglutinin glycoprotein binds to the host's surface sialic acid sugars, specifically on the surfaces of epithelial cells in the lung and throat (Stage 1 in infection figure). The cell imports the virus by endocytosis. In the acidic pH environment of the endosome, part of the hemagglutinin protein fuses the viral envelope with the vacuole's membrane, releasing: the viral RNA (vRNA) molecules, accessory proteins and RNA-dependent RNA polymerase into the host cell's cytoplasm (Stage 2). These proteins and vRNA form a complex that is transported into the host cell nucleus, where the host's own RNA-dependent RNA polymerase begins transcribing complementary positive-sense cRNA (Steps 3a and b). The cRNA is either exported into the cytoplasm and translated (step 4), or remains in the host nucleus. Newly synthesised viral proteins are either secreted through the Golgi apparatus onto the host cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported into the host nucleus, where they bind vRNA and form new viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading cellular mRNA and using those consequently-released nucleotides for vRNA synthesis, while also inhibiting translation of the host cell's mRNAs.
A virion assembles from negative-sense vRNAs (that form the genomes of newly created viruses), RNA-dependent RNA transcriptase and other viral proteins. Hemagglutinin and neuraminidase molecules cluster into a bulge in the host cell membrane. The vRNA and viral core proteins leave the nucleus and enter this membrane protrusion (step 6). The mature virus buds off from the host cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (step 7). As before, the viruses then adhere to the same host cell capsule through hemagglutinin; the mature viruses detach once their neuraminidase has cleaved sialic acid residues from the host cell. After the release of new influenza virus, the host cell dies, and infection repeats in other host cells.
Orthomyxoviridae viruses are one of two RNA viruses that replicate in the nucleus (the other being retroviridae). This is because the machinery of orthomyxo viruses cannot make their own mRNAs. They use cellular RNAs as primers for initiating the viral mRNA synthesis in a process known as cap snatching. Once in the nucleus, the RNA Polymerase Protein PB2 finds a cellular pre-mRNA and binds to its 5′ capped end. Then RNA Polymerase PA cleaves off the cellular mRNA near the 5′ end and uses this capped fragment as a primer for transcribing the rest of the viral RNA genome in viral mRNA. This is due to the need of mRNA to have a 5′ cap in order to be recognized by the cell's ribosome for translation.
Since RNA proofreading enzymes are absent, the RNA-dependent RNA transcriptase makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, nearly every newly manufactured influenza virus will contain a mutation in its genome. The separation of the genome into eight separate segments of vRNA allows mixing (reassortment) of the genes if more than one variety of influenza virus has infected the same cell (superinfection). The resulting alteration in the genome segments packaged into viral progeny confers new behavior, sometimes the ability to infect new host species or to overcome protective immunity of host populations to its old genome (in which case it is called an antigenic shift).
Classification In a phylogenetic-based taxonomy, RNA viruses include the subcategory negative-sense ssRNA virus, which includes the order Articulavirales, and the family Orthomyxoviridae. The family contains the following genera:
Alphainfluenzavirus (Influenza A virus} Betainfluenzavirus (Influenza B virus) Gammainfluenzavirus (Influenza C virus) Deltainfluenzavirus (Influenza D virus) Isavirus Mykissvirus Quaranjavirus Sardinovirus Thogotovirus
Epidemiology
Evolution and history
The predominant natural reservoir of influenza viruses is thought to be wild waterfowl. A 2023 involving total RNA sequencing and transcriptome mining found that Influenza viruses and the broader Articulavirales order likely had an aquatic origin, with fish being some of the earliest hosts, and the earliest viruses in the order evolving from Crustaceans over 600 million years ago. The subtypes of influenza A virus are estimated to have diverged 2,000 years ago. Influenza viruses A and B are estimated to have diverged from a single ancestor around 4,000 years ago, while the ancestor of influenza viruses A and B and the ancestor of influenza virus C are estimated to have diverged from a common ancestor around 8,000 years ago.
Outbreaks of influenza-like disease can be found throughout recorded history. The first probable record is by Hippocrates in 412 BCE. The historian Fujikawa listed 46 epidemics of flu-like illness in Japan between 862 and 1868. In Europe and the Americas, a number of epidemics were recorded through the Middle Ages and up to the end of the 19th century.In 1918–1919 came the first flu pandemic of the 20th century, known generally as the "Spanish flu", which caused an estimated 20 to 50 million deaths worldwide. It is now known that this was caused by an immunologically novel H1N1 subtype of influenza A. The next pandemic took place in 1957, the "Asian flu", which was caused by a H2N2 subtype of the virus in which the genome segments coding for HA and NA appeared to have derived from avian influenza strains by reassortment, while the remainder of the genome was descended from the 1918 virus. The 1968 pandemic ("Hong Kong flu") was caused by a H3N2 subtype in which the NA segment was derived from the 1957 virus, while the HA segment had been reassorted from an avian strain of influenza.
In the 21st century, a strain of H1N1 flu (since titled "H1N1pdm09") was antigenically very different from previous H1N1 strains, leading to a pandemic in 2009. Because of its close resemblance to some strains circulating in pigs, this became known as "swine flu".
Influenza A virus continues to circulate and evolve in birds and pigs. Almost all possible combinations of H (1 through 16) and N (1 through 11) have been isolated from wild birds. As of June 2024, two particularly virulent IAV strains - H5N1 and H7N9 – are predominant in wild bird populations. These frequently cause outbreaks in domestic poultry, with occasional spillover infections in humans who are in close contact with poultry.
Pandemic potential