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Pig Interferon Gene and Its Application in Disease Resistance Breeding
Interferon is one of the most important cytokines in animal organisms. At present, five kinds of porcine interferon (type I interferon α, β, ω, δ and type II interferon γ) have been found. This article lists the gene structure, antiviral and immunoregulatory functions of major porcine interferons (INFα, β, γ), and summarizes the antiviral mechanisms of interferon-mediated JAK-STAT signal transduction pathways in the body. The porcine interferon gene may have genetic polymorphism closely related to comprehensive disease resistance in pigs and its application prospect in pig disease resistance breeding. In 1957, Isaacs and Lindenman first discovered a type of soluble cell secretion that interferes with and inhibits viral replication in an influenza virus infection test of chicken embryo cells. It was named interferon. Wheelock and Green successively discovered in 1965 and 1969 that immunocompetent cells were stimulated by mitogens or antigens to produce an acid-sensitive interferon called immune interferon. At present, the sensitivity of interferon to acid is usually divided into type I interferon (acid sensitive) and type II interferon (acid resistant). Almost all vertebrates can produce these two types of interferons. According to the type of interferon-producing cells, type I interferons have so far found six types of INF-α, β, ω, κ, τ, δ, etc., and type II interference. Only one type of INF-γ has been found so far (Domeika, 2003). Due to its broad-spectrum, high-level antiviral function and its key regulatory role in the immune system, interferons have become one of the most active areas in immunology, genetics, and molecular biology. 2. Porcine interferon and its gene structure Currently found porcine interferons include INF-α, β, ω, δ, and INF-γ, and INF-δ is not found in other species (Domeika, 2003). Porcine INF-α and ω are protein families encoded by 12 and 5 or more related functional genes, respectively. The homology between the two subtypes of these two interferons is high, and the natural INF-α is often INF-α. A mixture of ω-functional gene expression products, whereas INF-β, δ, and INF-γ are only encoded by a single gene (Bonnardiere, et al., 1994). The porcine interferon genes that have now been cloned, sequenced, and localized include INF-α, β, ω, and INF-γ, and are summarized as follows: 3. Mechanism of interferon action 3.1. Main biological functions of interferons 3.1.1 Interference As one of the most important cytokines in the body, the main biological function of interferon is manifested in broad-spectrum antiviral activity and immunoregulatory function, and its action characteristics can be summarized as (Yang Yehwa, 2000; Zhou Guangyan, 2000): 1. Interferons are induced proteins, and normal cells do not generally produce interferons spontaneously. After being stimulated by an inducer (including viruses, bacteria, and certain chemical synthetic substances), the interferon gene is inhibited and expressed; The system is the first virus defense system that is currently known to play the fastest, can make the body in a very short period of time (a few minutes) in the anti-virus state, and the body is resistant to repeated infection of the virus in 1-3 weeks time The role of; 3, the antiviral effect of interferon is through the binding of the target cell receptor, induced indirect antiviral protein (AVP) play a role in inhibiting the virus instead of killing Extinction; 4. Interferon has species specificity, and different viruses and different cells have different susceptibility to interferon; 5. Type I and Type II interferons exert different effects and cannot be substituted for each other. 3.1.2. Main biological functions of interferon At present, there are many reports on the biological functions and mechanism of action of IFN-α, β and γ. The sources of type I and type II interferons are different (INF-α is mainly composed of mononuclear macrophages. In fact, INF-β is derived from fibroblasts, and INF-γ is mainly produced in αβ T cells, γδ T cells, and NK cells. There are some differences in the biological effects of volatility. The main biological function of interferon can be summarized as (Samuel, 2001): 1. Broad-spectrum antiviral function: Both type I and type II interferon genes can be expressed through the activation of the inducer, and the expression product passes through specific signal transduction pathways. Activate the transcription of interferon-inducible genes, the body synthesizes a variety of anti-viral enzymes and proteins that block the function of viral replication, resist the infection of the virus on the body cells; 2, immune regulatory function: type I interferon can enhance MHC-I molecules Expression, while strongly inhibiting the expression of MHC-II molecules; type II interferon can promote the expression of MHC-II molecules, the coordinated regulation of two types of interferon, so that the body is in the best immune response state. In addition, the production of INF-γ can promote the differentiation of Th0 cells into Th1 and inhibit the production of Th2. Since Th1 and Th2 mediate cellular and humoral immunity, INF-γ can be infected according to different pathogens and with other cytokines (eg, IL-4, etc.) work together to perform immune intervention on the body to achieve immune system defense function. 3. Immune enhancement: Both type I and type II interferons can stimulate NK cells and enhance their killing function, which is beneficial to the body's elimination of viral infections; in addition, INF-gamma is the major macrophage-activating factor (MAF). ), promote macrophage phagocytosis and inflammatory response, and can directly promote T, B cell differentiation and CTL maturation, stimulate B cells to secrete antibodies, thereby enhancing the body's immune function. 3.2. Interferon Antiviral Mechanism The activation and expression of interferon genes is the body's first viral defense system, which precedes the body's immune response. Although interferon has many other biological functions (such as regulation of the immune system, affecting cell growth, differentiation, and apoptosis, etc.), the non-specific inhibitory function of interferon on invading viruses has implications for the prevention and treatment of many diseases. major. According to studies related to humans and mice, the defense response of the interferon to the virus is mainly through signal transduction and transcription activation pathways, resulting in a series of genes that are regulated by interferon and generate a variety of enzymes and proteins that directly act on invading viruses. Protecting the body from infection, the JAK-STAT pathway is the main mode of interferon-mediated signal transduction and transcriptional activation (Samuel, 2001). JAK is a protein tyrosine kinase of the Janus family, including Jak-1, Jak-2, Jak-3, Tyk-2, STAT (signal transducer and activator of transcription) ie cell transduction and transcriptional activators (including STAT-1). STAT-2, STAT-3, STAT-4, STAT-5a, STAT-5b, STAT-6), in which Jak-1, Jak-2, Tyk-2 and STAT-1, STAT-2 are directly involved in the interference Mediates the JAK-STAT signal transduction pathway. The specific process of the JAK-STAT pathway can be expressed as (Zhou Guangyan, 2000; Samuel, 2001): (1) Firstly from the induced expression of INF-α/β and INF-γ respectively with the heterogeneous dimer receptor INFAR1-INFAR2 Initiate binding to the extracellular domain of INFGR1-INFGR2, thereby activating the protein tyrosine kinases Jak-1, Tyk-2 and Jak-1, Jak-2 linked to the intracellular region of both receptors; (2) STAT- 1. STAT-2 phosphorylates tyrosine at specific positions of the protein chain and forms heterodimers under the catalytic action of Jak-1 and Tyk-2, and then forms three with interferon regulatory factor-9 (INF-9). Aggregates, while two molecules of STAT-1 form homodimers under the action of Jak-1 and Jak-2; (3) formed trimers and homodimers with the ISRE element and GAS element of the chromosome, respectively Binding, which activates a variety of antiviral gene promoters, generates a variety of antiviral proteins and participates in the body's rapid defense of virus defense. The antiviral proteins induced by interferon mainly include: (Yang Yeh-hua, 2000; Samuel, 2001) (1) Double-stranded RNA-dependent protein kinase (PKR, often called P1/eIF-2α), whose main function is to block Host cell mRNA synthesis of viral proteins; (2) 2,5-oligoadenylate synthetase (OAS), the main function of activation of endogenous RNase L, active RNase L can degrade viral mRNA; (3) Adenosine deaminase 1 (ADAR1) can modify the base A of viral RNA to I and prevent viral protein synthesis; (4) Mx protein (a GTP-binding protein) that can bind to viral nucleoprotein The damage of the viral capsid protein; (5) nitric oxide synthase (NOS), can make the body produce NO, NO can play an important role in immune defense. 4. Prospects for the application of interferon genes in pig disease resistance breeding 4.1. Genetic basis of livestock and poultry disease resistance traits Resistance to most diseases and other important economical traits belong to the same quantitative traits and are affected by multiple genes and environment. The common effects (Axford et al., 2000). Studies have shown that there are additive genetic variances in the disease resistance traits of most respiratory tract and digestive tract diseases in livestock and poultry: Lundheim estimates the susceptibility of Swedish herds to respiratory diseases by 0.14, and the susceptibility to atrophic rhinitis by estimating the hereditary variance components of males. The h2 is 0.16 (1979); the h2 of intestinal disease is 0.59 (1988). Pryztulski and Porzeczkowska (1980) estimated the resistance of pigs to the spirochetes was 0.20-0.21; Bumstead et al. (1991) analyzed the inbreds of eight different chickens against seven different species of coccidiosis and salmonella. The resistance of Escherichia coli, Marek’s disease virus, infectious bronchitis virus and five avian leukosis viruses showed that the resistance of various inbred strains to pathogens was different. The results showed that the disease resistance of livestock and poultry was mostly affected by multiple genes. And environmental effects have a common effect. Although the multi-gene effect of quantitative traits lays a theoretical foundation for the breeding of disease-specific pathogens in pigs, there are still problems to be solved in the practice of breeding. The specific manifestations are as follows: (1) Direct resistance to specific diseases The cost of the selection and the loss caused to the production are extremely large; (2) the resistance to a certain pathogen may cause susceptibility to other pathogens; (3) the indirect selection of the resistance to a specific pathogen essentially leads to The simultaneous and positive selection of the viability of the pathogen itself hindered the selection of disease resistance of livestock and poultry (Gandon et al., 2001). Therefore, it is important for animal and poultry breeding research to have an integrated, disease-free, and pathogen-free comprehensive defense capability for livestock and poultry, and to search for comprehensive resistance genes (QTL) or genetic markers. It is important to develop comprehensive breeding methods for livestock and poultry. 4.2. Relationship between interferon and disease resistance The strong antiviral and multiple immune regulatory functions of interferon make the interferon gene an ideal candidate gene for pig disease resistance selection. So far, studies on the correlation analysis of genetic polymorphisms of porcine interferon genes and comprehensive disease resistance have not been reported. However, research reports on the correlation analysis of human disease and interferon gene polymorphisms may be useful for future studies on pig disease resistance selection. For example, different IFN-γ genotypes are significantly associated with the susceptibility of domestic kidney disease in Japan (Masutani Et al., 2003); IFN-γ gene has a single nucleotide marker associated with the human pneumonia susceptible group (Lopez-Maderuelo et al., 2003); human susceptibility to hepatitis B virus and IFN-γ gene expression Differences were related (Ben-Ari et al., 2003); Lio et al. (2002), Stassen et al. (2002), and Lu et al. (2002) also reported similar findings. In addition, a large number of in vivo and in vitro tests have shown that porcine interferon has a defensive and inhibitory effect on infectious disease viruses that pose a major threat. A series of in vitro experiments showed that treatment of PRRSV (proliferative and respiratory syndrome virus) porcine macrophages with IFN-γ inhibited PRRSV proliferation (Bautista & Molitor, 1999); after treatment of Marc-145 cells with recombinant interferon-γ , inhibits the proliferation of PRRSV wild-type strains and cell-adapted strains (Rowland, 2001); porcine IFN-α/β can effectively inhibit the viability of foot-and-mouth disease virus (Chinsangaram et al., 1999); porcine recombinant IFN-γ can inhibit Viral replication in porcine epithelial cells and lung macrophages infected with transmissible gastroenteritis coronavirus (Charley B, et al, 1988); porcine INF-gamma inhibits monocyte and pulmonary macrophages infected with swine fever virus Viral replication (Esparza et al, 1988). Animal studies in vivo have demonstrated that simultaneous administration of swine fever vaccine and interferon enhances the ability against swine fever virus (Suradhat, et al. 2001); piglets infected with TGEV can rapidly produce anti-TGEV IFN in intestinal epithelium. -α (Riffault et al., 2001).