Interferon, Mx, and viral countermeasures

The interferon system provides a powerful and universal intracellular defense mechanism against viruses. Knockout mice defective in IFN signaling quickly succumb to all kinds of viral infections. Likewise, humans with genetic defects in interferon signaling die of viral disease at an early age. Among the known interferon-induced antiviral mechanisms, the Mx pathway is one of the most powerful. Mx proteins belong to the dynamin superfamily of large GTPases and have direct antiviral activity. They inhibit a wide range of viruses by blocking an early stage of the viral replication cycle. Likewise, the protein kinase R (PKR), and the 2–5 OAS/RNaseL system represent major antiviral pathways and have been extensively studied. Viruses, in turn, have evolved multiple strategies to escape the IFN system. They try to go undetected, suppress IFN synthesis, bind and neutralize secreted IFN molecules, block IFN signaling, or inhibit the action of IFN-induced antiviral proteins. Here, we summarize recent findings about the astonishing interplay of viruses with the IFN response pathway.     

干扰素及其基因工程

1　概述Ｚｓｓａｃｓ和Ｌｉｎｄｅｎｍａｎｎ于 185 7年首先发现受到病毒感染的细胞能产生一种物质 ,可以保护其它细胞抗御多种病毒的感染 ,并命名为干扰素。现定义为 :由干扰素诱导剂作用于活细胞后 ,由活细胞产生的一种蛋白质 ,当它再作用于其他细胞时 ,使其它细胞立即获得抗病毒和抗肿瘤等多方面的免疫力。病毒、细菌、立克次图 1　干扰素的作用机制氏体、真菌以及原虫等都能诱导细胞产生干扰素。细菌的内毒素、外毒素、放线菌素Ｄ(ａｃｔｉｎｏｍｙｃｉｎＤ)等也能诱导产生干扰素。人工合成的物质如聚次黄嘌呤核苷酸 (聚肌苷酸 ) :聚胞…     

Interferon and Interferon Inducers in Protozoal Infections

Several interferon inducers (Newcastle disease virus, statolon, and poly rI:poly rC) as well as exogenous mouse interferon protect mice from sporozoite-induced Plasmodium berghei malaria, as long as they are administered before the end of the preerythrocytic phase of development of the parasite. The protective effect of the interferon inducers was related to their interferon-inducing effect; the protective effect of the interferon preparations was related to the interferon titer of the preparations, and it exhibited other attributes of interferon such as species specificity. In contrast to sporozoite-induced infection, blood forms-induced P. berghei malaria was only weakly susceptible to the protective effect of interferon inducers. This difference may provide an approach to study the mechanism of protection. The growth in cell cultures of another intracellular protozoon, Toxoplasma gondii, is also inhibited by interferon (22). The fact that P. berghei and T. gondii (as well as another group of intracellular parasites susceptible to interferon, the Chlamydia) have their own ribosomes raises questions, concerning the role of host cell ribosomes in the host cell-parasite relationship of these intracellular parasites and in the mechanism of interferon action against them, that can be approached experimentally. The possibility of therapeutic or prophylactic application of interferon or of its inducers to certain protozoal diseases of man and of other animals is still remote, but it has to be considered for long range planning.     

Semi-Micro, Dye-Binding Assay for Rabbit Interferon

A technique is described for the demonstration of bacterial capsules by using montmorillonite in combination with a conventional staining method.     

Interferon,restriction factors and SUMO pathways

SUMOylation is a reversible post-translational modification that regulates several cellular processes including protein stability, subcellular localization, protein–protein interactions and plays a key role in the interferon (IFN) pathway and antiviral defense. In human, three ubiquitously expressed SUMO paralogs (SUMO1, 2 and 3) have been described for their implication in both intrinsic and innate immunity. Differential effects between SUMO paralogs are emerging such as their distinctive regulations of IFN synthesis, of IFN signaling and of the expression and function of IFN-stimulated gene (ISG) products. Several restriction factors are conjugated to SUMO and their modifications are further enhanced in response to IFN. Also, IFN itself was shown to increase global cellular SUMOylation and requires the presence of the E3 SUMO ligase PML that coordinates the assembly of PML nuclear bodies. This review focuses on differential effects of SUMO paralogs on IFN signaling and the stabilization/destabilization of ISG products, highlighting the crosstalk between SUMOylation and other post-translational modifications such as ubiquitination and ISGylation.     

Enhancement of Interferon Production in a Mouse Cell Line, a High-Yielding Source of Mouse Interferon

Priming with interferon prior to poly(I).poly(C) treatment of a mouse cell line, MO 57/2, followed by sequential administration of metabolic inhibitors, resulted in the production of high yields of mouse interferon.     

Interferon and Interferon Inducers in the Treatment of Malignancies

The mechanism of the antitumor action of polyinosinic-polycytidylic acid is probably multifaceted. The compound induces the synthesis of interferon, and interferon probably is active against some tumors. Poly I:poly C alters protein and RNA synthesis in tissue culture. It specifically inhibits such macromolecule synthesis in tumors in vivo, while having less inhibitory action on synthesis in normal organs, or it may actually enhance. Finally, poly I:poly C strongly enhances graft vs. host rejection mechanisms, which may play a role in the rejection of some tumors.     

Interferon in pregnancy

The cells of the immune system exchange information by a complex network of molecules referred to as lymphokines: these include the interferons. The physiology of the interferons, both in terms of control and function, is poorly understood. However, there is ample evidence that production of alpha-interferon is characteristic of the fetoplacental unit in both the human and other species. Indeed, the major trophoblast protein in early pregnancy in the sheep is alpha-interferon and in this species the molecule appears to have an important anti-luteolytic effect. The function of the interferons in human pregnancy is not known but, by analogy with information from other experimental systems, it might reflect aspects of the immune relationship between the mother and the fetus.     

Nonviral Interferon Inducers

Interferon production can be stimulated by a great variety of microbial and nonmicrobial agents other than viruses. The nonmicrobial inducers can be divided into polyanions, mitogens, and a miscellaneous category including the various endotoxins and antibiotics. The polyanions appear to require a stable, high molecular weight backbone and a high density of free anionic groups whether they are polynucleotides, plastics, or polysaccharides. Mitogen-induced interferon appears to be but one of a constellation of substances produced following lymphocyte transformation. The process of transformation can be stimulated either by specific immune recognition or non-specifically by phytohemagglutinin. Synthetic polynucleotide inducers are active; the thermostable, double-stranded RNA''s are much more active than the double-stranded DNA''s or 1-, 3-, or 4-stranded RNA''s. Some success has been obtained with potentiation of nucleotide inducers through the use of polycationic substances, complexing with a polysaccharide, concurrent administration of a metabolic antagonist, or substitution of phosphate by thiophosphate in the polynucleotide backbone. The stages in the interaction of interferon stimulating RNA and cells can be divided into three steps: first, binding to cell surface, next, a temperature dependent "recognition" step, and finally, degradation and utilization of monomers in cellular RNA synthesis; the critical recognition site has not yet been determined. The vast majority of cell-associated polynucleotide remains at the surface of the cell. Information from animal models resembling human diseases suggests that certain of these nucleotide inducers may have clinical usefulness in therapy or prophylaxis.