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Interferon and Nonviral Pathogens
Gerald. I. Bryne, Jenifer Turco
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eBook - ePub
Interferon and Nonviral Pathogens
Gerald. I. Bryne, Jenifer Turco
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This book explores the important role of the interferons in infections due to nonviral intracellular pathogens. It deals with the induction of interferons by a variety of intracellular microorganisms and the effects of interferons on the host cells and the microorganisms.
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Part I
THE INTERFERON SYSTEM
1
Interferons and Their Induction
I. INTRODUCTION
Since the original demonstration of interferon by Issacs and Lindenmann (1) 30 years ago, in which a factor released by chicken egg chorioallantoic membranes exposed to heat-inactivated influenza virus was shown to inhibit the replication of live virus, the complexity and impact of the interferon system has expanded substantially. Several excellent reviews (2-5) have been written concerning inter-ferons and their physical characteristics, inducers and mechanisms of induction, mechanisms of regulation of production, genetics, and their biological activities. Since an all-inclusive review of the interferon system is beyond the scope of this chapter, its purpose will be to present a general overview of interferons and their induction processes.
II. PHYSICAL CHARACTERISTICS OF INTERFERONS
Interferons are defined as inducible proteins that inhibit viral replication. Additional characteristics which serve to distinguish interferons from antibodies and nonspecific inhibitors of viral growth include several biological and physico-chemical criteria (Table 1). Interferons are divided into three main classes, α, ÎČ, and Îł (Table 2). Although immunologically distinct, the type I interferons, interferon α and interferon ÎČ, share many characteristics and have been shown to be physicochemically related (7), with approximately 30% shared amino acid sequence and with 46% DNA sequence homology. It is speculated that these two interferon classes arose from a common ancestral gene 5-10 Ă 10s years ago. Interferon Îł (type II) is both antigenically and genetically distinct from type I interferons (8,9) although a common evolutionary ancestor for type I and type II interferons has been proposed (10).
Biological criteria |
1. Inducible protein which inhibits replication of a broad range of viruses, both DNA and RNA. |
2. Virus replication is inhibited intracellularly through a process that involves de novo cellular RNA and protein synthesis. |
3. Antiviral effects of interferons from individual vertebrates each have characteristic and limited host range specificities. |
Physicochemical criteria |
1. Protein with antigenic crossâreactivity with known interferon. |
2. Amino acid or DNA sequence similar to known interferon. |
3. Antiviral effects mediated through activation of 2â5 A synthetase. |
Source: Adapted from Ref. 6.
Class | |||
---|---|---|---|
Characteristic | α | ÎČ | Îł |
Synonym | leukocyte | fibroblast | immune |
lymphoblastoid | type I | type 11 | |
type 1 | |||
Cell source | leukocytes | fibro blasts | T lymphocytes |
lymphoblastoid cells | NK cells | ||
Molecular weight | 18,000â22,000 | 20,000â25,000 | 20,000â25,000 |
pH 2 stable | yes/no | yes | no |
Heat stable (56°C for 30 min) | yes | yes | no |
Glycosylation | no | yes | yes |
Species number | 20 | 1â5 | 1 |
Introns | no | no/yes | yes |
Chromosomal location | 9 | 9,7,5,2 | 12 |
A. Interferon α
Interferon α (IFNα) represents a family of related interferons produced by leukocytes and lymphoblastoid celllines in response to virus infection (11), hence its former names âleukocyte interferonâ and âlymphoblastoid interferon.â The human interferon α species are physicochemically heterogeneous when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), affinity chromatography, isoelectric focusing, or high performance liquid chromatography (HPLC) (12-20), and display a range of molecular weights, from 18,000 to 22,000. Since most IFNα species are not glycosylated (21,22), heterogeneity in molecular weight is due to differences in structure and amino acid sequence. Interferon a is characterized further by its acid stability at pH 2. One exception is a recently described species of interferon α found in the circulation of patients with the immune system disorders, systemic lupus erythematosus (SLE), acquired immunodeficiency syndrome (AIDS), generalized lymphadenopathy, and juvenile arthritis (23-27). Although interferon obtained from the serum of these patients is characterized as interferon a by neutralization assays with anti-IFNα antibody, it is acid labile. This species also can be obtained from normal donor blood, produced either by Sendai virus-induced polymorpho-nuclear cells or produced spontaneously in culture upon incubation of a subfraction of large granular lymphocytes (28,29). The exact relationship of acid-labile interferon α to other IFNa species awaits further characterization.
More than 20 interferon a genes and pseudogenes (αx, α2, α3, etc.) have been identified (30-35) and classified into two large subfamilies based on amino acid replacement (36). Amino acid sequences of interferon α species derived from virus-induced leukocyte mRNAs show about 80% homology and nucleotide sequences show 90% homology (34,37,38). On the basis of this homology, it has been calculated that the human interferon a genes diverged 2-3 à 10s years ago. Mature interferon a polypeptides are 165 or 166 amino acids in length. Somatic cell hybridization studies have shown that all human interferon a genes reside on chromosome 9 (39,40).
B. Interferon ÎČ
Although interferon ÎČ also is secreted by virus-induced leukocytes (although to a lesser degree) (41), it is the major class of interferon generated by polyribo-nucleotide-induced fibroblasts. Purified natural interferon ÎČ1 has a molecular weight of approximately 20,000-25,000 daltons (42-44). Its amino acid sequence has been determined from cloned cDNA (45-47) and IFNÂČ1 shows homology with IFN± at both the amino acid and nucleotide level (7). Its similarity to interferon ± does not end at the sequence level. Interferon ÂČ is also 166 amino acids in length and also contains no introns in its genetic structure (48,49). Not only is it acid stable like interferon ±, but it also binds to the same receptor (50). However, unlike IFNa, interferon ÎČ1 produced by eukaryotic cells is glycosylated (51).
In addition to interferon ÎČ1, up to six additional interferon-ÂČ mRNAs have been described (52). Only one of their products, interferon ÎČ2, has been characterized sufficiently to compare to interferon ÎČ1. The physicochemical relationship of interferon ÎČ2 to interferon ÎČ1 is still being elucidated. Although initial identification of interferon ÎČ2 was based on its neutralization and precipitation by polyclonal anti-IFN0 (53,54), highly specific anti-IFN/ÎČ1 antibody fails to precipitate IFN/ÂČ2 (55). Furthermore, mRNAs specific to interferon ÎČ2 and inter-feron ÎČ2 fail to cross-hybridize, indicating a lack of homology between mRNA sequences (53,54). The interferon ÎČ2-specific mRNA codes for a 26,000 dalton primary transcript (54). This polypeptide is glycosylated and cleaved to a 21,000-22,000 dalton product (55), approximately 180-184 amino acids in length (56), before secretion from the cell. The gene coding for the 26,000 molecular weight protein has been sequenced (56). Approximately 20% amino acid homology has been defined between interferon ÎČ1, and interferon ÎČ2 (57) with similarities especially in the region of interferon ÎČ1 amino acids 42-52 (54), which contains conserved sequences between IFNa: and IFN/ÎČ1. Unlike IFN/α, the IFN/ÎČ2 gene sequence is interrupted by at least three introns (56-58). The sequence of interferon ÎČ2 has been shown to be identical to the reported sequence of human B-cell differentiation factor (BCDF or BSF-2) (59).
Some investigations have failed to induce antiviral activity with translation products of IFN/ÎČ2 mRNA (55); others have induced antiviral activity with similar preparations (53,54,58). In addition, antiviral activity induced by tumor necrosis factor (TNF) has been shown to be neutralized by antisera to IFNÎČ2. Blot hybridization analysis has shown that TNF induces IFNÎČ2 mRNA, but not IFNÎČ1 mRNA (60). It has been speculated that differences in biological inter-feron assay system sensitivities may account for the conflicting results obtained from various laboratories (56).
Characterizations of genomic clones and chromosomal mapping studies have demonstrated that the interferon ÎČ1 gene is present on human chromosome 9 (39,40,61), the same chromosome which contains the interferon a gene family. Similarly, both the murine interferon ÎČ1 and interferon a genes have been located on mouse chromosome 4 (62,63). However, somatic cell hybridization studies have indicated that human interferon ÎČ genes exist on at least three chromosomes, 2, 5, and 9 (64,65). Chromosomal mapping using blot hybridization has located the interferon ÎČ2 gene on human chromosome 7 (66). Whether or not additional interferon ÎČ species can be matched to chromosomes 2 and 5 awaits further experimentation.
C. Interferon Îł
Although interferon Îł has been distinguished classically from type I interferons (IFNa and IFN]3) on the basis of its inactivation by pH 2 acid treatment or 56°C heat treatment (67), it differs in many of its physicochemical characteristics. It is typically produced during immune responses (67,68), hence its former name âimmune interferon.â T lymphocytes, including helpe3r and cytotoxic/suppressor...