正黏液病毒科

形态学

流行性感冒病毒系依其基质蛋白（matrix protein）及内部核糖核蛋白（ribonucleoprotein；可溶性抗原）之抗原特性而分为A、B及C三种，外层蛋白包括血球凝集素（hemagglutinin，HA）及神经氨酸酶（neuraminidase, NA）两种，也为组成流行性感冒的抗原成分。流行性感冒病毒依其血球凝集素及神经胺酸酶之抗原性不同可再分为数种亚型，现今已知血球凝集素已有十六种（H1-H16），神经胺酸酶则有九种。C型流行性感冒之化学性及结构性与A 及 B 型流行性感冒皆十分相似，但它缺少神经胺酸酶，只有血球凝集素酶一种，在病毒表面上具有一特殊的接受器（receptor），使病毒表面呈蜂窝状，而 A 型及B 型流行性感冒很少呈蜂窝状。
流行性感冒病毒在电子显微镜下有丝状及多形性二种，但大部分为多形性，负染色时常为70 - 120 nm 之圆形颗粒。新分离的流行性感冒病毒颗粒，其大小及形状皆不一致，丝状者经常可长达几百奈米（nanometer），甚至长达4,000 nm，有时可以见到一些奇形怪状者，流行性感冒病毒与其它病毒不同的是它的整个病毒表面有约略等距间隔的突起，一种为长约10 - 14 nm，宽约4 nm ，横切面为三角形，含有血球凝集素的杆状突起，另一为长约9 nm，宽约5 nm，含有神经胺酸酶的圆柱状突起。
在针状突起层下面为一包围基质蛋白及核酸蛋白之脂质被膜， A型流行性感冒病毒之核蛋白衣（nucleocapsid）含有与病毒RNA 相连的RNA 聚合酶， B 型及C 型流行性感冒病毒之核蛋白衣亦可能有相同的结构。病毒封套（envelope）厚度为6 至 8  nm，当封套破裂或染色液渗入时，可能会看到核酸呈折叠状平行的条状结构。以清洁剂处理也可能会得到大小不等的极度卷曲形状的核蛋白衣。
C 型流行性感冒病毒外型与A或B型结构大致相同，不容易区分，有时可见病毒表面有六角型的结构，通常在电子显微镜下，同一视野中可能会同时见到这两种不同形状的病毒颗粒。
血球凝集素可附着于不同动物的红血球，而使红血球凝集，而神经胺酸酶与病毒离开寄主细胞有关，神经胺酸酶会分解膜上的神经胺酸，而使病毒由寄主细胞脱离感染其他细胞。 C 型流行性感冒病毒也含有可破坏流行性感冒接受器的酶，但它与神经胺酸酶不同。

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Genome

Viruses of this family contain 6 to 8 segments of linear negative-sense single stranded RNA.
The total genome length is 12000–15000 nucleotides (nt). The largest segment 2300–2500 nt; of second largest 2300–2500 nt; of third 2200–2300 nt; of fourth 1700–1800 nt; of fifth 1500–1600 nt; of sixth 1400–1500 nt; of seventh 1000–1100 nt; of eighth 800–900 nt. Genome sequence has terminal repeated sequences; repeated at both ends. Terminal repeats at the 5'-end 12–13 nucleotides long. Nucleotide sequences of 3'-terminus identical; the same in genera of same family; most on RNA (segments), or on all RNA species. Terminal repeats at the 3'-end 9–11 nucleotides long. Encapsidated nucleic acid is solely genomic. Each virion may contain defective interfering copies.

Structure

The following applies for Influenza A viruses, although other influenza strains are very similar in structure:
The influenza A virus particle or virion is 80–120 nm in diameter and usually roughly spherical, although filamentous forms can occur.Unusually for a virus, the influenza A genome is not a single piece of nucleic acid; instead, it contains eight pieces of segmented negative-sense RNA (13.5 kilobases total), which encode 11 proteins (HA, NA, NP, M1, M2, NS1, NEP, PA, PB1, PB1-F2, PB2).The best-characterised of these viral proteins are hemagglutinin and neuraminidase, two large glycoproteins found on the outside of the viral particles. Neuraminidase is an enzyme involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles.  By contrast, hemagglutinin is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell.The hemagglutinin (H) and neuraminidase (N) proteins are targets for antiviral drugs.These proteins are also recognised by antibodies, i.e. they are antigens.The responses of antibodies to these proteins are used to classify the different serotypes of influenza A viruses, hence the H and N in H5N1.

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. Flu viruses can remain infectious for about one week at human body temperature, over 30 days at 0 °C（32 °F）, and indefinitely at very low temperatures (such as lakes in northeast Siberia). They can be inactivated easily by disinfectants and detergents.
The viruses bind to a cell through interactions between its hemagglutinin glycoprotein and sialic acid sugars 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 endosome, part of the haemagglutinin 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 cytoplasm (Stage 2).These proteins and vRNA form a complex that is transported into the cell nucleus, where the 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 nucleus. Newly synthesised viral proteins are either secreted through the Golgi apparatus onto the cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to 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 the released nucleotides for vRNA synthesis and also inhibiting translation of host-cell mRNAs.
Negative-sense vRNAs that form the genomes of future viruses, RNA-dependent RNA transcriptase, and other viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in the 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 cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (step 7).As before, the viruses adhere to the cell 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.
Orthomyxoviridae viruses are one of the only RNA viruses that replicate in the nucleus. 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).

Types

There are three genera of influenza virus: Influenzavirus A, Influenzavirus B and Influenzavirus C. Each genus includes only one species, or type: Influenza A virus, Influenza B virus, and Influenza C virus, respectively. Influenza A and C infect multiple species, while influenza B almost exclusively infects humans.

Influenza B

Influenza B virus is almost exclusively a human pathogen, and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal.This type of influenza mutates at a rate 2–3 times lower than type Aand consequently is less genetically diverse, with only one influenza B serotype.As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible.This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.

Influenza C

The influenza C virus infects humans and pigs, and can cause severe illness and local epidemics.However, influenza C is less common than the other types and usually seems to cause mild disease in children.

Viability and disinfection

Mammalian influenza viruses tend to be labile, but can survive several hours in mucus.Avian influenza virus can survive for 100 days in distilled water at room temperature, and 200 days at 17 °C（63 °F）. The avian virus is inactivated more quickly in manure, but can survive for up to 2 weeks in feces on cages. Avian influenza viruses can survive indefinitely when frozen.Influenza viruses are susceptible to bleach, 70% ethanol, aldehydes, oxidizing agents, and quaternary ammonium compounds. They are inactivated by heat of 133 °F（56 °C） for minimum of 60 minutes, as well as by low pH <2.

Vaccination and prophylaxis

Vaccines and drugs are available for the prophylaxis and treatment of influenza virus infections. Vaccines are composed of either inactivated or live attenuated virions of the H1N1 and H3N2 human influenza A viruses, as well as those of influenza B viruses. Because the antigenicities of the wild viruses evolve, vaccines are reformulated annually by updating the seed strains.
However, when the antigenicities of the seed strains and wild viruses do not match, vaccines fail to protect the vaccinees. In addition, even when they do match, escape mutants are often generated. Drugs available for the treatment of influenza include Amantadine and Rimantadine, which inhibit the uncoating of virions by interfering with M2, and Oseltamivir (marketed under the brand name Tamiflu), Zanamivir, and Peramivir, which inhibit the release of virions from infected cells by interfering with NA. However, escape mutants are often generated for the former drug and less frequently for the latter drug.

流行病学

台湾于1972年时首次发现家禽流行性感冒病毒感染症，血清型为H6N1 ，现今在台湾H血清型共十型(H1,2,3,4,6,7,8,10,11,14)， N血清型共八型(N1,2,3,4,6,7,8,9) ，其组合共十五种。A型流行性感冒病毒对猪而言，可造成严重的增殖性坏死性肺炎。