Interferon type I in protective body reactions in an experimental Klebsiella infection]

The study on mice with experimental generalized Klebsiella infection, carried out with the use of microbiologic, immunologic and pathomorphologic methods, revealed that the intraperitoneal injection of type I interferon into the animals prevented their death and led to the rapid elimination of the infective agent from their body, enhanced the phagocytic and metabolic activity of polymorphonuclear lymphocytes of their peritoneal exudate, decreased the manifestation of microcirculatory and dystrophic changes in the parenchyma of their internal organs.     

The yin and yang of type I interferon activity in bacterial infection

Interferons (IFNs) are cytokines that are important for immune responses, particularly to intracellular pathogens. They are divided into two structurally and functionally distinct types that interact with different cell-surface receptors. Classically, type I IFNs are potent antiviral immunoregulators, whereas the type II IFN enhances antibacterial immunity. However, as outlined here, type I IFNs are also produced in response to infection with other pathogens, and an increasing body of work shows that type I IFNs have an important role in the host response to bacterial infection. Strikingly, their activity can be either favourable or detrimental, and can influence various immune effector mechanisms.     

Effect of interferon type I on the in vivo persistence of Salmonella typhimurium

The influence of type I interferon on the persistence of S. typhimurium in the body of mice has been studied. The injection of the preparation of interferon has been shown to be conductive to the survival of the animals and to reduce the time of Salmonella persistence in the body. The injection of interferon enhances the phagocytic activity of macrophages in the peritoneal exudate of mice.     

汉坦病毒感染对Ⅰ型干扰素应答的调节机制

汉坦病毒主要感染人内皮细胞,细胞在病毒感染早期诱导生成的Ⅰ型干扰素(IFN-Ⅰ)可阻断汉坦病毒的复制,但不同的病毒蛋白和不同型别的汉坦病毒在IFN应答的调节机制上可能有所不同。就汉坦病毒感染对IFN应答的调节机制进行了综述。     

Exhaustion of type I interferon response following an acute viral infection

Viral infections often cause a period of heightened susceptibility to a secondary infection but the cause of this phenomenon is unknown. We found that a primary viral infection in mice rapidly triggers an IFN-I-dependent partial activation state in the majority of B and T lymphocytes, which reverts to a resting phenotype within 5 days. When a secondary infection with an unrelated virus occurred 5 to 9 days after the primary infection, no recurrence of marked activation of lymphocytes was observed. This was not due to an inherent inability of the previously activated cells to undergo renewed partial activation, because they responded when challenged with virus after transfer into "naive" recipients. Instead, the failure to respond optimally resided in the original host's incapacity to mount an IFN-I response to the secondary infection during this time period. Thus, transient immunosuppression through exhaustion of IFN-I production during an acute viral infection creates a time period of enhanced susceptibility to secondary infection.     

Schmallenberg virus infection of adult type I interferon receptor knock-out mice

Schmallenberg virus (SBV), a novel orthobunyavirus, was discovered in Europe in late 2011. It causes mild and transient disease in adult ruminants, but fetal infection can lead to abortion or severe malformations. There is considerable demand for SBV research, but in vivo studies in large animals are complicated by their long gestation periods and the cost of high containment housing. The goal of this study was to investigate whether type I interferon receptor knock-out (IFNAR(-/-)) mice are a suitable small animal model for SBV. Twenty IFNAR(-/-) mice were inoculated with SBV, four were kept as controls. After inoculation, all were observed and weighed daily; two mice per day were sacrificed and blood, brain, lungs, liver, spleen, and intestine were harvested. All but one inoculated mouse lost weight, and two mice died spontaneously at the end of the first week, while another two had to be euthanized. Real-time RT-PCR detected large amounts of SBV RNA in all dead or sick mice; the controls were healthy and PCR-negative. IFNAR(-/-) mice are susceptible to SBV infection and can develop fatal disease, making them a handy and versatile tool for SBV vaccine research.     

The human type I interferon gene cluster

The human type I interferon genes are clustered on the short arm of chromosome 9, at band 9p21. The structure of this gene cluster has been recently determined, and is described. The organization of the genes, and their divergence in sequence give clues about the possible mechanisms that were involved in the evolution of the type I interferons. TheIFNAgenes andIFNWpseudogenes can be separated in two groups: a distal group of 10 genes and pseudogenes, that has a more recent origin, and a proximal group of 13 genes and pseudogenes, which expanded earlier in the evolution of the cluster.     

Lipid peroxidation in experimental Salmonella infection

The results of investigation of lipid peroxidation in experimental Salmonella infection in 21-day-old rabbits are analyzed. Salmonella infection was accompanied by activation of lipid peroxidation not only in enterocytes, but also in blood serum. An increase in the level of malonic dialdehyde leads to a decrease in the antioxidation capacity and in the peroxidation resistance of erythrocytic membranes. The severity of the pathological process was found related to the activity of lipid peroxidation.     

Dissection of a type I interferon pathway in controlling bacterial intracellular infection in mice

Defence mechanisms against intracellular bacterial pathogens are incompletely understood. Our study characterizes a type I IFN-dependent cell-autonomous defence pathway directed against Legionella pneumophila, an intracellular model organism and frequent cause of pneumonia. We show that macrophages infected with L. pneumophila produced IFNβ in a STING- and IRF3- dependent manner. Paracrine type I IFNs stimulated upregulation of IFN-stimulated genes and a cell-autonomous defence pathway acting on replicating and non-replicating Legionella within their specialized vacuole. Our infection experiments in mice lacking receptors for type I and/or II IFNs show that type I IFNs contribute to expression of IFN-stimulated genes and to bacterial clearance as well as resistance in L. pneumophila pneumonia in addition to type II IFN. Overall, our study shows that paracrine type I IFNs mediate defence against L. pneumophila, and demonstrates a protective role of type I IFNs in in vivo infections with intracellular bacteria.     

Effects of interferon preparations on the course of Salmonella infection (experimental and clinical studies)]

The effect of type I interferons on the process of experimental salmonellosis in mice and rabbits, as well as their effect on salmonellosis in patients was studied. It was shown that homologous interferon increased the animal survival rate, activated bactericidal activity of the phagocytic cells and increased elimination of the infectious agents from the host. The complex of the etiotropic and pathogenetic treatment of 32 patients with salmonellosis included human leukocytic interferon, leukinferon. It was administered intramuscularly in a dose of 1 x 10(4)-2 x 10(4) IU: three injections at intervals of 48 to 72 hours (the treatment course). The course was repeated 10 days after the last injection of the first course. Addition of leukinferon to the routine scheme of the medicinal treatment of salmonellosis provided recovery of all the patients without complications or appearance of the bacteria carriers (the observation period of more than 3 years).     

Rinderpest virus blocks type I and type II interferon action: role of structural and nonstructural proteins

Rinderpest virus (RPV) is a paramyxovirus closely related to the human pathogen Measles virus. It causes severe disease in cattle, buffalo, and some wild animals; although it can infect humans, it does not cause disease. Here, we demonstrate that RPV blocks the action of both type I (alpha) and type II (gamma) interferons (IFNs) by blocking the phosphorylation and nuclear translocation of STAT1 and STAT2 and that this block is not related to species specificity. In addition, both wild-type virulent and vaccine strains of the virus blocked IFN action. Unlike the case with some other paramyxoviruses, neither STAT1 nor STAT2 is degraded upon virus infection. STAT1 is bound by both the viral structural protein P, and thereby recruited to concentrations of viral protein in the cell, and the nonstructural protein V. Although both P and V proteins bind to STAT1 and can block IFN action when expressed in transfected cells, the IFN antagonist activity of the P protein is weaker than that of the V protein. The viral C protein also seems to weakly block IFN-induced activation of STAT1 in transfection experiments. However, studies with knockout viruses showed that the viral V protein appears to be the dominant inhibitor of IFN signaling in the context of virus infection, since prevention of viral V expression restored the IFN sensitivity of infected cells. Although a change in the distribution pattern of STAT2 was observed in virus-infected cells, STAT2 was not bound by any viral protein.     

The protective properties of different Legionella antigens in experimental Legionella infection

The protective properties of Legionella antigenic preparations were studied on guinea pigs with experimental Legionella infection. Preliminary immunization of guinea pigs with serotypic antigen, cytolysin, as well as live or formalin-treated Legionella cells, did not protect the animals from the subsequent aerogenic infection with 10(5) colony-forming units of virulent L. pneumophila. Immunization with the main outer membrane protein ensured the survival of 70% of the animals and inhibited the proliferation of the infective agent in the lungs of guinea pigs subjected to aerogenic infection with 10(5) colony-forming units of virulent L. pneumophila. The data obtained in this study indicate that the main outer membrane protein of L. pneumophila is capable of stimulating protective immunity.     

The evolution of the type I interferon gene family in mammals

A phylogenetic analysis of mammalian type I interferon (IFN) genes showed: (1) that the three main subfamilies of these genes in mammals (IFN-, IFN-, and IFN-) diverged after the divergence of birds and mammals but before radiation of the eutherian orders and (2) that IFN- diverged first. Although apparent cases of interlocus recombination among mouse IFN- genes were identified, the hypothesis that coding regions of IFN- genes have been homogenized within species by interlocus recombination was not supported. Flanking regions as well as coding regions of IFN- were more similar within human and mouse than between these species; and reconstruction of the pattern of nucleotide substitution in IFN- coding regions of four mammalian species by the maximum parsimony method suggested that parallel substitutions have occurred far more frequently between species than within species. Therefore, it seems likely that IFN- genes have duplicated independently within different eutherian orders. In general, type I IFN genes are subject to purifying selection, which in the case of IFN- and IFN- is strongest in the putative receptor-binding domains. However, analysis of the pattern of nucleotide substitution among IFN- genes suggested that positive Darwinian selection may have acted in some cases to diversify members of this subfamily at the amino acid level.     

Critical role of constitutive type I interferon response in bronchial epithelial cell to influenza infection

Innate antiviral responses in bronchial epithelial cells (BECs) provide the first line of defense against respiratory viral infection and the effectiveness of this response is critically dependent on the type I interferons (IFNs). However the importance of the antiviral responses in BECs during influenza infection is not well understood. We profiled the innate immune response to infection with H3N2 and H5N1 virus using Calu-3 cells and primary BECs to model proximal airway cells. The susceptibility of BECs to influenza infection was not solely dependent on the sialic acid-bearing glycoprotein, and antiviral responses that occurred after viral endocytosis was more important in limiting viral replication. The early antiviral response and apoptosis correlated with the ability to limit viral replication. Both viruses reduced RIG-I associated antiviral responses and subsequent induction of IFN-β. However it was found that there was constitutive release of IFN-β by BECs and this was critical in inducing late antiviral signaling via type I IFN receptors, and was crucial in limiting viral infection. This study characterizes anti-influenza virus responses in airway epithelial cells and shows that constitutive IFN-β release plays a more important role in initiating protective late IFN-stimulated responses during human influenza infection in bronchial epithelial cells.     

Differential roles of type I interferon signaling in tumor versus host cells in experimental glioma models

Despite multimodal treatment approaches including surgery, radiotherapy and chemotherapy, the median survival for patients with glioblastoma remains in the range of one year and thus poor. Type I interferons (IFN) are involved in immune responses to viral infection and exhibit anti-tumor activity in certain cancers.Here we explored the biological relevance of constitutive type I IFN signaling in murine glioma models in vitro and in vivo. CT-2A, GL-261, SMA-497, SMA-540 and SMA-560 murine glioma cells expressed IFN type I receptors IFNAR1 and IFNAR2 and were responsive to exogenous IFN stimulation. CRISPR/Cas9-mediated deletion of IFNAR1 decreased the baseline expression of type I IFN response genes in GL-261 cells, but neither in CT-2A nor in SMA-560 cells. IFNAR1 deletion slowed growth in GL-261 and SMA-560, but not in CT-2A cells. However, only the growth of IFNAR1-depleted GL-261 tumors and not that of SMA-560 tumors was delayed in vivo upon orthotopic tumor cell implantation into syngeneic mice. This survival gain was no longer detected when the IFNAR1-depleted GL-261 cells were inoculated into IFNAR1-deficient mice. Altogether these data suggest that constitutive type I IFN signaling in gliomas may be pro-tumorigenic, but only in a microenvironment that is proficient for type I IFN signaling in the host.     

Immunomodulating action of interferon in congenital and experimental thymus-dependent immunodeficiency

A study of immunomodulating action of mouse alpha/beta interferon (IFN) was performed in conditions of congenital and experimental thymus-dependent immune deficiency. The action of IFN was assessed in vivo, with IFN injected intraperitoneally. It was shown that IFN did not change killer effect of lymphocytes in the reaction of stem cell inactivation in "nude" mice, but enhanced antibody and rosette formation in the spleen of these animals. In addition, IFN did not change these parameters in the spleen of HRS mice with abnormal differentiation of T lymphocytes, but enhanced antibody and rosette formation in the spleen of mice, thymectomized in old age. It is concluded that the normal function of T-system is essential for the action of IFN.     

Fine tuning type I interferon responses

Interferon responses are balanced between protection against pathogens and other disease agents versus toxicity and development of chronic diseases. Optimal outcomes are achieved by regulating the nature, strength and duration of Interferon (IFN) production, IFN-receptor interaction and signalling pathways modulated in a manner appropriate for particular target cells. Modification of cell behaviour is mediated by regulation of positive and negative signalling pathways and by proteins encoded by selected groups of IFN-regulated genes. Understanding how these pathways are regulated and how to measure them by biomarkers or gene signatures will enable us to better understand the role of IFN pathways in the pathogenesis of infectious and inflammatory diseases and cancer. This will lead to improved patient stratification and disease treatment.     

The pathogenetic bases for chemotherapy in an experimental Salmonella infection]

The effect of etiotropic (polymyxin and adriblastin) and pathogenetic (levamisole and vitamin E) chemotherapy on lipid peroxidation (LPO), phagocyte functional activity and the process and outcomes of Salmonella infection was studied in rabbits. It was shown that development of salmonellosis was accompanied by activation of LPO which was phase-by-phase. There was synchronism in changing of LPO and neutrophilic phagocytic activity. Adriblastin and levamisole stimulated LPO and increased the neutrophilic phagocytic activity. Vitamin E inhibited LPO and had an unfavourable effect on the process and outcomes of the infection. The problem in differential use of the chemotherapeutic drugs with an account of their modulating effect on LPO is discussed.