Article

Virus Interference. I. The Interferon

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Abstract

During a study of the interference produced by heat-inactivated influenza virus with the growth of live virus in fragments of chick chorio-allantoic membrane it was found that following incubation of heated virus with membrane a new factor was released. This factor, recognized by its ability to induce interference in fresh pieces of chorio-allantoic membrane, was called interferon. Following a lag phase interferon was first detected in the membranes after 3 h incubation and thereafter it was released into the surrounding fluid.

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... An early example of the development of cytokine-based therapies to augment the host antiviral response was the use of type I interferons (Fig. 1). Although the first studies demonstrating their ability to induce an antiviral state in cells were carried out in the late 1950s 4 , randomized controlled trials of the use of interferons to treat viral infections or where sterile cure is not achieved by drug treatment such as in people living with HIV-1. Moreover, in the case of tuberculosis (TB), where poorly tolerated antimicrobial drugs need to be delivered for many months, leading to poor compliance, host-directed therapies administered on their own or adjunctively may contribute to shorter and more effective treatment. ...
... Robert S. Wallis 1,2,3,4 ✉ , Anne O'Garra 5,6 , Alan Sher 7 and Andreas Wack 8 ✉ 1 The Aurum Institute, Johannesburg, South Africa. 2 Vanderbilt University, Nashville, TN, USA. 3 Rutgers University, Newark, NJ, USA. 4 Case Western Reserve University, Cleveland, OH, USA. 5 Immunoregulation and Infection Laboratory, The Francis Crick Institute, London, UK. 6 National Heart and Lung Institute, Imperial College London, London, UK. 7 Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 8 Immunoregulation Laboratory, The Francis Crick Institute, London, UK. ...
... Robert S. Wallis 1,2,3,4 ✉ , Anne O'Garra 5,6 , Alan Sher 7 and Andreas Wack 8 ✉ 1 The Aurum Institute, Johannesburg, South Africa. 2 Vanderbilt University, Nashville, TN, USA. 3 Rutgers University, Newark, NJ, USA. 4 Case Western Reserve University, Cleveland, OH, USA. 5 Immunoregulation and Infection Laboratory, The Francis Crick Institute, London, UK. 6 National Heart and Lung Institute, Imperial College London, London, UK. 7 Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 8 Immunoregulation Laboratory, The Francis Crick Institute, London, UK. ...
Article
The advent of COVID-19 and the persistent threat of infectious diseases such as tuberculosis, malaria, influenza and HIV/AIDS remind us of the marked impact that infections continue to have on public health. Some of the most effective protective measures are vaccines but these have been difficult to develop for some of these infectious diseases even after decades of research. The development of drugs and immunotherapies acting directly against the pathogen can be equally challenging, and such pathogen-directed therapeutics have the potential disadvantage of selecting for resistance. An alternative approach is provided by host-directed therapies, which interfere with host cellular processes required for pathogen survival or replication, or target the host immune response to infection (immunotherapies) to either augment immunity or ameliorate immunopathology. Here, we provide a historical perspective of host-directed immunotherapeutic interventions for viral and bacterial infections and then focus on SARS-CoV-2 and Mycobacterium tuberculosis, two major human pathogens of the current era, to indicate the key lessons learned and discuss candidate immunotherapeutic approaches, with a focus on drugs currently in clinical trials. In this Perspective, the authors reflect on the historical development of host-directed immunotherapeutic interventions for viral and bacterial infections, and then focus on how historical insights can be applied to current approaches to therapy of SARS-CoV-2 and Mycobacterium tuberculosis infections.
... During a study of the disturbance produced by heat-inactivated influenza virus with the growth of live virus in fragments of chick chorioallantoic membrane, interferon was first found to be inhibiting the growth of influenza virus [7] . Thus, Interferon was discovered by the phenomenon of viral interference and for many years considered to be exclusively an antiviral substance. ...
Chapter
Interferons are the crucial components of the immune system of vertebrate animals. The studies regarding mammalian interferons are extensive and serve as a model to study and find similar functional counterparts in aquatic vertebrates such as the fishes. There are three different varieties of interferon families reported and IFN-ɣ is having a crucial role in immune response and is used as an immune adjuvant in gene vaccines. The detailed literature regarding the various studies of interferons is dealt with in this chapter.
... 40,41 This process generates transcription factors (e.g., NF-κB), which induce the expression of types I and III interferons (IFN) that interfere with the viral replication. 42 The IFN activate the JAK-STAT signaling pathway and induce the expression of antiviral genes, whose products (i) restricts the viral replication within infected cells, (ii) induces an "antiviral state" in the tissue by recruiting cells of the innate immune system and (iii) prepare an adaptive immune response. 43 However, the SARS-CoV-2 infection is effective in delaying or preventing the production of immune responses associated with types I and III IFN, thus enabling the viral replication to proceed uncontested and delay the activation of the innate immune system. ...
Article
COVID‐19 is a dynamic disease and may affect different tissues and organs as it progresses. Therefore, the impact generated by the disease in all its stages and organs requires a functional and versatile imaging technique able to detect particularities or artifacts dynamically. Ultrasonography fulfills all these requirements and exhibit several advantages relative to other imaging modalities, including portability, lower cost and biosafety. Throughout the COVID‐19 pandemic, ultrasonography displayed a crucial role in the triage, monitoring, indicating organ damages and enabling individualized therapeutical decisions in COVID‐19 patients. This review is dedicated to highlight the main pathological effects correlated with ultrasound changes caused by COVID‐19 in the lungs, heart and liver. This review is dedicated to highlight the main pathological effects correlated with ultrasound changes caused by COVID‐19 in the lungs, heart and liver.
... IFNs were initially discovered to be an antiviral factor released from chick chorio-allantoic membranes infected with influenza viruses (32). More than 30 years later, STAT1, STAT2, and IRF9 were identified as transcription factors of IFN-I signaling (33,34). ...
Article
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Interferons (IFNs) have broad-spectrum antiviral activity to resist virus epidemic. However, IFN antiviral efficacy needs to be greatly improved. Here, we reveal that LATS1 is a vital signal transmitter governing full type-I IFN (IFN-I) signaling activity. LATS1 constitutively binds with the IFN-I receptor IFNAR2 and is rapidly tyro-phosphorylated by Tyk2 upon IFN-I engagement. Tyro-phosphorylation of LATS1 promotes LATS1 activation and YAP degradation, thereby promoting IFN-mediated antiproliferation activity. Moreover, activated LATS1 translocates into the nucleus and induces CDK8-Ser62 phosphorylation, which in turn phosphorylates STAT1 at Ser727 and induces full IFN-I antiviral activity. LATS1 deficiency restricts in vivo IFN-I signaling and attenuates host antiviral immune response. Our study identifies IFN-I as a previously unidentified extracellular diffusible ligand signal for activation of the Hippo core LATS1 pathway and reveals Tyk2-LATS1-CDK8 as a complete signaling cascade controlling full IFN-I activity.
... interfere with viral infection in cells (Isaacs and Lindenmann 1957). They both act in an autocrine and paracrine manner by binding to the heterodimeric IFN-α/β receptor (IFNAR) (Uzé et al. 1990, Novick et al. 1994, Domanski et al. 1995. ...
Thesis
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Recognition of conserved molecular patterns by pattern recognition receptors (PRRs) is crucial for the initiation of an innate immune response. Within PRRs, the NOD-like receptor (NLR) family is, in humans, a group of 22 cytosolic proteins, which function as PRRs of the innate immune system and as regulators of adaptive immune responses. However, it has become evident, that several NLR proteins also function as regulators of innate immune responses. In this thesis the function of human NLR proteins NLRC5 and NLRP11 in immune responses was further characterized. The first part of this thesis was focused on the NOD-like receptor NLRC5. NLRC5 and major histocompatibility complex (MHC) class II transcriptional activator (CIITA) are the master regulators of MHC class I and II transcription, respectively. Both proteins can translocate into the nucleus, where they induce transcription of MHC class I and class II, respectively. As NLRC5 and CIITA do not possess intrinsic DNA binding capacities, they exert their function by binding to a common multiprotein complex, termed MHC enhanceosome and through recruitment of further transcriptional regulators. Although MHC enhanceosome components are, as known thus far, identical, NLRC5 and CIITA are specific for their respective transcriptional targets. In this work we employed several techniques to identify novel interaction partners of NLRC5 to understand the mechanisms behind this specificity. As the N-terminal domain death-domain like fold (DD) of NLRC5 has previously been shown to be involved in conferring specificity, we adapted a protocol for proximal ligation by fusion of the NLRC5 DD to biotin ligase from Aquifex aeolicus (BioID2) to unravel the interactome of this NLRC5 domain. By enrichment of biotinylated proteins through streptavidin-biotin precipitation and analysis of the proteins by LC-MS/MS, we aimed to identify novel putative interactors with functions in transcriptional regulation. Additionally, we used yeast 2 hybrid screening of the NLRC5 DD against a library of human CD4+ and CD8+ T cells for the identification of novel interaction partners. This led to the identification of the paired amphipathic helix protein Sin3A (Sin3A) and the negative elongation factor B (NELFB) as interactors of NLRC5 DD. Characterization of their role in transcriptional regulation of MHC class I revealed an inhibitory role of both proteins. However, as we also observed repression of CIITA-mediated MHC class II transcription, both proteins are likely not involved in determination of target specificity of NLRC5. Translocation of NLRC5 into the nucleus is essential for the induction of MHC class I transcription. It has however previously been shown, that forced nuclear localization of NLRC5 strongly diminishes its transcriptional activity. We therefore employed co-immunoprecipitation of differentially localized NLRC5 constructs to identify interaction partners which might be involved in post translational regulation of NLRC5. Further, to advance our understanding of the NLRC5 DD, we aimed to elucidate its crystal structure. For this, we established a protocol for large-scale recombinant expression and purification of the NLRC5 DD for subsequent crystallization of the recombinant protein. The second part of this thesis was focused on NLRP11. Tight regulation of inflammatory cytokine and interferon (IFN) production in innate immunity is pivotal for optimal control of pathogens and avoidance of immunopathology. NLRP11 has previously been shown to regulate type I IFN and other pro-inflammatory responses. To gain a deeper understanding of the underlying mechanism, we aimed to identify novel NLRP11 interactors, through which the inhibition is conferred. Here we generated cell lines stably expressing NLRP11-eGFP as novel tools to elucidate the functions of NLRP11. We identified the ATP-dependent RNA helicase DDX3X as a novel binding partner of NLRP11 by co immunoprecipitation and LC-MS/MS. DDX3X is known to enhance type I IFN responses and NLRP3 inflammasome activation. We demonstrate that NLRP11 can abolish IKKe-mediated phosphorylation of DDX3X, resulting in lower type I IFN induction upon viral infection. These effects were dependent on the leucine-rich repeat (LRR) domain of NLRP11 that we mapped as the interaction domain for DDX3X. In addition, NLRP11 also suppressed NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting, that NLRP11 might sequester DDX3X and prevent it from promoting NLRP3-induced inflammasome activation. Taken together, our data revealed DDX3X as a central target of NLRP11, which can mediate the effects of NLRP11 on type I IFN induction, as well as NLRP3 inflammasome activation. This expands our knowledge of the molecular mechanisms underlying NLRP11 function in innate immunity and suggests that both NLRP11 and DDX3X might be promising targets for modulation of innate immune responses.
... Unfortunately, the use of bacterial toxins as (immuno-)'therapy" was quickly frowned upon, especially since the mechanism of tumor regression was not well understood at the time. Other modalities, such as radiation and newly developed small molecule drugs remained the fashion until almost 100 years later and the discovery of interferon and other cytokine immune stimulants like Interleukin-2 (IL-2) (37)(38)(39)(40)(41). While IFN and IL-2 were initially touted as game changers in tumor therapy, they came crashing to unceremonious endings based on unexpected toxicities and paradoxical immune-suppression mechanisms in the clinic. ...
Article
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For many years, cell-surface glycans (in particular, Tumor-Associated Carbohydrate Antigens, TACAs) have been the target of both passive and active anticancer immunotherapeutic design. Recent advances in immunotherapy as a treatment for a variety of malignancies has revolutionized anti-tumor treatment regimens. Checkpoint inhibitors, Chimeric Antigen Receptor T-cells, Oncolytic virus therapy, monoclonal antibodies and vaccines have been developed and many approvals have led to remarkable outcomes in a subset of patients. However, many of these therapies are very selective for specific patient populations and hence the search for improved therapeutics and refinement of techniques for delivery are ongoing and fervent research areas. Most of these agents are directed at protein/peptide epitopes, but glycans–based targets are gaining in popularity, and a handful of approved immunotherapies owe their activity to oligosaccharide targets. In addition, nanotechnology and nanoparticle-derived systems can help improve the delivery of these agents to specific organs and cell types based on tumor-selective approaches. This review will first outline some of the historical beginnings of this research area and subsequently concentrate on the last 5 years of work. Based on the progress in therapeutic design, predictions can be made as to what the future holds for increasing the percentage of positive patient outcomes for optimized systems.
... [40][41][42] Type-1 IFNs are composed of IFNα and IFNß, and are involved in anti-viral responses by activating NK cells. 43,44 However, their role in T-cell activation is controversial: Type-1 interferons can facilitate antigen presentation to T-cells and maximize T-cell mediated antitumor immunity, 45,46 however chronic type-1 interferon signals also recruit MDSC and Treg, and induce expression of inhibitory molecules, such as PD-L1 or IDO. 47,48 Our RNA sequencing studies identified that stimulation with single versus a combination of TLR agonists affected the activation of both of these different cytokine pathways. ...
Article
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We previously found that activated CD8+ T-cells increase expression of PD-1, which can be attenuated in the presence of specific Toll-like receptor (TLR) agonists, mediated by IL-12 secreted by professional antigen-presenting cells. While these CD8+ T-cells had greater anti-tumor activity, T-cells stimulated by different TLR had different gene expression profiles. Consequently, we sought to determine whether combinations of TLR agonists might further affect the expression of T-cell checkpoint receptors and improve T-cell anti-tumor immunity. Activation of CD8+ T-cells in the presence of specific TLR ligands resulted in decreased expression of PD-1, LAG-3, and CD160, notably with combinations of TLR1/2, TLR3, and TLR9 agonists. Immunization of E.G7-OVA or TRAMP-C1 tumor-bearing mice with peptide or DNA vaccines, co-administered with combination of TLR3 and TLR9 agonists, showed greater suppression of tumor growth. The anti-tumor effect of TLR1/2 and/or TLR9, but not TLR3, was abrogated in IL-12KO mice. RNA sequencing of TLR-conditioned CD8+ T-cells revealed IL-12 pathway activation, and type 1 IFN pathway activation following TLR3 stimulation. Our results provide a mechanistic rationale for the choice of optimal combinations of TLR ligands to use as adjuvants to improve the efficacy of anti-tumor vaccines.
... In the 1950s, in the course of their studies on the structures and properties of influenza A and other viruses, Alick Isaacs and Jean Lindenmann discovered a soluble factor that was produced by virus-infected cells and could inhibit viral infection; they named this compound "interferon" (IFN) for its capacity to "interfere" with viral replication [1,2]. There are currently three known types of IFN: I, II, and III, which are classified by their sequence and cellular receptors [3,4]. ...
Article
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Immune checkpoint blockade (ICB) therapies have achieved remarkable clinical responses in patients with many different types of cancer; however, most patients who receive ICB monotherapy fail to achieve long-term responses, and some tumors become immunotherapy-resistant and even hyperprogressive. Type I interferons (IFNs) have been demonstrated to inhibit tumor growth directly and indirectly by acting upon tumor and immune cells, respectively. Furthermore, accumulating evidence indicates that endo- and exogenously enhancing type I IFNs have a synergistic effect on anti-tumor immunity. Therefore, clinical trials studying new treatment strategies that combine type I IFN inducers with ICB are currently in progress. Here, we review the cellular sources of type I IFNs and their roles in the immune regulation of the tumor microenvironment. In addition, we highlight immunotherapies based on type I IFNs and combination therapy between type I IFN inducers and ICBs.
... IFN-I was discovered in 1957 by Isaacs and Lindenmann as a factor capable of interference with viruses [107]. Later, in 1974, Lindenmann suggested that viruses could be used as immunological adjuvants in cancer, based on his studies on viral oncolysis and post-oncolytic immunity [108]. ...
Article
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Oncolytic viruses represent interesting anti-cancer agents with high tumor selectivity and immune stimulatory potential. The present review provides an update of the molecular mechanisms of the anti-neoplastic and immune stimulatory properties of the avian paramyxovirus, Newcastle Disease Virus (NDV). The anti-neoplastic activities of NDV include (i) the endocytic targeting of the GTPase Rac1 in Ras-transformed human tumorigenic cells; (ii) the switch from cellular protein to viral protein synthesis and the induction of autophagy mediated by viral nucleoprotein NP; (iii) the virus replication mediated by viral RNA polymerase (large protein (L), associated with phosphoprotein (P)); (iv) the facilitation of NDV spread in tumors via the membrane budding of the virus progeny with the help of matrix protein (M) and fusion protein (F); and (v) the oncolysis via apoptosis, necroptosis, pyroptosis, or ferroptosis associated with immunogenic cell death. A special property of this oncolytic virus consists of its potential for breaking therapy resistance in human cancer cells. Eight examples of this important property are presented and explained. In healthy human cells, NDV infection activates the RIG-MAVs immune signaling pathway and establishes an anti-viral state based on a strong and uninhibited interferon α,ß response. The review also describes the molecular determinants and mechanisms of the NDV-mediated immune stimulatory effects, in which the viral hemagglutinin-neuraminidase (HN) protein plays a prominent role. The six viral proteins provide oncolytic NDV with a special profile in the treatment of cancer.
... Interferons (IFNs) comprise a family of cytokines first described in 1957 (2). The name was originally due to their ability to inhibit viral replication within cells. ...
Article
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In solid tumors, as the tumor grows and the disease progresses, hypoxic regions are often generated, but in contrast to most normal cells which cannot survive under these conditions, tumour cells adapt to hypoxia by HIF-driven mechanisms. Hypoxia can further promote cancer development by generating an immunosuppressive environment within the tumour mass, which allows tumour cells to escape the immune system recognition. This is achieved by recruiting immunosuppressive cells and by upregulating molecules which block immune cell activation. Hypoxia can also confer resistance to antitumor therapies by inducing the expression of membrane proteins that increase drug efflux or by inhibiting the apoptosis of treated cells. In addition, tumor cells require an active interferon (IFN) signalling pathway for the success of many anticancer therapies, such as radiotherapy or chemotherapy. Therefore, hypoxic effects on this pathway needs to be addressed for a successful treatment.
... The first step in determining that SLE is a disease of the immune system was taken in 1948 when Hargraves et al. discovered the lupus erythematosus cell phenomenon [21]. In 1957, Issacs and Lindenmann discovered that in cell culture, heat-inactivated influenza virus induces a soluble factor that inhibits propagation of live influenza virus; they named this factor IFN [22]. SLE is characterized by dysregulation in both the innate and adaptive immune systems, and type I IFNs serve as a class of cytokines that bridges innate and adaptive immunity [23]. ...
Article
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Dysregulation of type I interferons (IFNs) has been implicated in the pathogenesis of sys-temic lupus erythematosus (SLE) since the late 1970s. The majority of SLE patients demonstrate evidence of type I IFN pathway activation; however, studies attempting to address the relationship between type I IFN signature and SLE disease activity have yielded conflicting results. In addition to type I IFNs, type II and III IFNs may overlap and also contribute to the IFN signature. Different genetic backgrounds lead to overproduction of type I IFNs in SLE and contribute to the breakdown of peripheral tolerance by activation of antigen-presenting myeloid dendritic cells, thus triggering the expansion and differentiation of autoreactive lymphocytes. The consequence of the continuous stimulation of the immune system is manifested in different organ systems typical of SLE (e.g., mu-cocutaneous and cardiovascular involvement). After the discovery of the type I IFN signature, a number of different strategies have been developed to downregulate the IFN system in SLE patients, finally leading to the successful trial of anifrolumab, the second biologic to be approved for the treatment of SLE in 10 years. In this review, we will discuss the bench to bedside translation of the type I IFN pathway and put forward some issues that remain unresolved when selecting SLE patients for treatment with biologics targeting type I IFNs.
... First recognized over 60 yr ago for their capacity to interfere with viral replication (Isaacs and Lindenmann, 1957), type I interferons (IFN-I) are essential for antiviral immunity (reviewed in Duncan et al., 2021). Virtually all human viral pathogens encode molecules designed to evade or subvert IFN-I responses (reviewed in Hoffmann et al., 2015;Randall and Goodbourn, 2008). ...
Article
Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro-a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.
... IFNs were discovered by Issac and Lindenmann in 1957 [6] . They were first isolated from natural sources and later on from recombi-two other studies were published. ...
Article
We conducted an experimental protocol with a nasal recombinant IFNα-2b formulation (Nasalferon) in 12 healthy volunteers who received 1 MIU per nostril twice a day, three consecutive days, and studied the induction of biomarkers related to antiviral and immune responses. Nasalferon increases the antiviral biomarker OAS1 transcript levels in oropharynx and PBMCs, regulates molecular and cellular elements related to innate and adaptive immune responses and decreases granulocytes population. These effects support Nasalferon use in virally-exposed populations.
... In 1989, Bielefeldt et al (1989), stated that "the use of recombinant cytokines for treatment of livestock disease has not progressed very far" (Bielefeldt Ohmann, et al. 1989, Wood andSeow 1996). Indeed, since the discovery of interferon (IFN), in 1957, the notion of using a cytokine in treating disease has been contemplated, however, progression during this time was limited (Isaacs andLindenman 1957, Vilcek andFeldmann 2004). Early trials involving the use of IFN showed some promise, however, due to the lack of modern advanced expression and purification methods, no uncontaminated preparations of a single isotype of IFN were obtained (Strander, et al. 1973). ...
Thesis
The prophylactic of use in-feed antibiotics and chemical based medicines such as anthelmintic are commonly used in order to maintain health and promote growth in food production animals. The inclusion of low regular or sub-therapeutic doses of antimicrobials in animal feed increases their efficiency to digest food by suppressing sensitive gut flora and reducing infection caused by opportunistic pathogenic organisms which could be detrimental to both the animal’s health and productivity. This practice has been linked to the emergence of drug resistant organisms, many of which are resistant to antibiotics commonly used in human medicine, posing a threat to both animals and humans (Hu). To reduce this threat, an alternative method of therapeutic treatment in food production animals must be developed. One suggestion is to enhance the animal’s own immune system, Hematopoiesis is the process of developing mature WBC from hematopoietic stem cells (HSC) within the bone marrow (BM). Therefore an understanding of hematopoiesis in pigs may uncover new therapeutic treatments. Cytokines are signalling molecules released by stimulated white blood cells (WBC), which activate essential cells and pathways essential in an innate or adaptive immune response to infection. These proteins initiate proliferation, differentiation and maturation of immature immune cells and precursors within the BM. Cytokines may therefore provide a viable alternative to current therapeutic practices. Although, many cytokines have been identified in Hu and mice (Mo), few have been studied in pigs. The cytokines of the common β subunit (CD131), interleukin-3 (IL-3), interleukin-5 (IL-5) and granulocyte, macrophage colony stimulating factor (GM-CSF) may prove to be valuable therapeutics. This unique group of cytokines not only share the same receptor subunit, but are involved in the production of several cells types. With this in mind, these cytokines, along with CD131, were analysed in silico, in vitro and in vivo. In silico phylogenetic analysis confirmed these cytokines in pigs developed similarly to other mammals. Molecular modelling suggests that structural changes due to altered genetic sequences, along with differences in CD131 binding residues, may result in a lack of cross species activity. The recombinant (rec) form of each porcine (Po) cytokine was produced and biological activity confirmed. In vitro analysis for rPoGMCSF and rPoIL-3 showed maturation of immature CD90+ and CD172a+ BM cells resulting in monocyte and macrophage development. Moreover, rPoIL-5 induced proliferation and maturation for eosinophils. To assess the activity of each cytokine in vivo, pigs were administered the chemotherapeutic drug, 5-flurouricil (5-FU) to produce a state of myelosuppression. The in vivo activity was examined on BM and peripheral white blood cells (WBC). rPoGM-CSF induced proliferation of CD90+ and CD172a+ cells within the BM resulting in increased platelets whilst rPoIL-3 was also shown to significantly increase basophil levels. More importantly, all 3 cytokines increased levels of eosinophils at different stages throughout the trial, with rPoIL-5 inducing the highest eosinophil production. These results suggest that these Po cytokines may have potential as therapeutics to enhance immunity in pigs, specifically in parasite infections. This report has analysed the activity of rPoIL-3, rPoIL-5 and rPoGM-CSF. In doing so, we have identified some of the roles of these cytokines in hematopoiesis. Furthermore, we have demonstrated the involvement of all three cytokines in the regulation of eosinophils and confirmed the role of PoIL-5 as the major eosinophilopoietin in the production of eosinophils in pigs
... Type I IFNs play a crucial role in the fight against viral infections [35], and in this study we assessed whether this heavy metal affect its induction/synthesis. Release of IFNβ was investigated using a sandwich enzyme immunoassay, whereas induction of both IFN-α1 and IFNβ Fig. 3. Cd 2+ levels in wild boar's liver and kidney from a polluted area of Liguria. ...
Article
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Cadmium (Cd²⁺) is regarded as one of the most toxic heavy metals, which can enter the food chain through environmental contamination and be bioaccumulated. Its exposure in Ligurian wild boars was monitored between 2016-2020 and revealed high level of this heavy metal in different provinces. In one of these polluted area, 21 wild boars were additionally sampled and the relationship between hepatic and renal Cd²⁺ concentration suggested that majority of these animals presented chronic intoxication. Cd²⁺ exposure of wild boar might lead to an immunosuppression status, thus in vitro experiments on wild boar monocyte-derived macrophages (moMФ) were carried out. Effects of Cd²⁺ scalar doses were evaluated through viability and adsorption assays, ELISA, qPCR. Moderate doses of this environmental pollutant (20 μM) were absorbed by moMФ, with subsequent reduction of their viability. This heavy metal did not trigger release of either IFN-β, anti-inflammatory or pro-inflammatory cytokines by moMФ, instead 24 h treatment with 20 μM of Cd²⁺ resulted in down-regulated expression of TNF-α, IL-12p40, several TLRs, CD14, MD2, BD2, MyD88, p65, and NOS2. The results of our monitoring activity suggested that wild boar can be useful to monitor environmental exposure of this heavy metal and can help in understanding the type of contamination. In addition, in vitro experiments on wild boar moMФ revealed that Cd²⁺ exposure negatively affected the immune function of these cells, likely leading to increased susceptibility to infection.
... Interferons (IFNs) are a family of cytokines that elicit pleiotropic biological effects and can be synthesized and secreted by most cell types. These proteins are characterized by antiviral activity, discovered in 1957 by Isaacs and Lindenmann [1] during studies on virus interference. They are considered the first line of defense initiated by cells during viral infections; on the whole, they show three major biological activities including antiviral, antitumor and immunomodulatory effects [2][3][4]. ...
Article
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Interferons (IFNs) are a family of cytokines that play a pivotal role in orchestrating the innate immune response during viral infections, thus representing the first line of defense in the host. After binding to their respective receptors, they are able to elicit a plethora of biological activities, by initiating signaling cascades which lead to the transcription of genes involved in antiviral, anti-inflammatory, immunomodulatory and antitumoral effector mechanisms. In hindsight, it is not surprising that viruses have evolved multiple IFN escape strategies toward efficient replication in the host. Hence, in order to achieve insight into preventive and treatment strategies, it is essential to explore the mechanisms underlying the IFN response to viral infections and the constraints thereof. Accordingly, this review is focused on three RNA and three DNA viruses of major importance in the swine farming sector, aiming to provide essential data as to how the IFN system modulates the antiviral immune response, and is affected by diverse, virus-driven, immune escape mechanisms.
... Type I IFNs are polypeptides that exhibit antiviral properties and were first described over 60 years ago (23). Subsequently, these polypeptides were found to play the critical roles in inflammation, cancer, and autoimmune diseases (10,21,24). ...
Article
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Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (MDA5 ⁺ DM) is typically characterized by cutaneous manifestations, amyopathic or hypomyopathic muscle involvement, and a high incidence of rapid progressive interstitial lung disease (RP-ILD). However, the exact etiology and pathogenesis of this condition has yet to be fully elucidated. Melanoma differentiation-associated gene 5 (MDA5), as the autoantigen target, is a member of the retinoic acid-inducible gene-I (RIG-I) family. The MDA5 protein can function as a cytosolic sensor that recognizes viral double-strand RNA and then triggers the transcription of genes encoding type I interferon (IFN). Therefore, it was presumed that viruses might trigger the overproduction of type I IFN, thus contributing to the development of MDA5 ⁺ DM. Emerging evidence provides further support to this hypothesis: the increased serum IFNα level was detected in the patients with MDA5 ⁺ DM, and the type I IFN gene signature was upregulated in both the peripheral blood mononuclear cells (PBMCs) and the skin tissues from these patients. In particular, RNA sequencing revealed the over-expression of the type I IFN genes in blood vessels from MDA5 ⁺ DM patients. In addition, Janus kinase (JAK) inhibitors achieved the promising therapeutic effects in cases with interstitial lung disease (ILD) associated with MDA5 ⁺ DM. In this review, we discuss the role of the type I IFN system in the pathogenesis of MDA5 ⁺ DM.
... The intrinsic ability of cells to recognize and respond to pathogens represents a hallmark of innate immunity, and innate immune sensing triggers orchestration of transcriptional regulation. A core component of the response to viral pathogens is signaling by type I interferons (IFNs) (Isaacs and Lindenmann, 1957), which include the IFN-a family of proteins encoded by thirteen different genes and IFN-b encoded by the IFNB1 gene (Wang and Fish, 2019). Type I IFN genes encode cytokines, which elicit signaling through binding to the IFNAR1 and 2 receptor complex, hence initiating a signaling cascade resulting in massive induction of interferon-stimulated genes (ISGs) (Rusinova et al., 2013). ...
Article
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The innate immune system represents a balanced first line of defense against infection. Type I interferons (IFNs) are key regulators of the response to viral infections with an essential early wave of IFN-β expression, which is conditional, time-restricted, and stochastic in its nature. The possibility to precisely monitor individual cells with active IFNB1 transcription during innate signaling requires a robust reporter system that mimics the endogenous IFN-β signal. Here, we present a reporter system based on expression of a destabilized version of eGFP (d2eGFP) from a stably integrated reporter cassette containing the IFNB1 promoter and 3’-untranslated region, enabling both spatial and temporal detection of regulated IFNB1 expression. Specifically, this reporter permits detection, quantification, and isolation of cells actively producing d2eGFP in a manner that fully mimics IFN-β production allowing tracking of IFNB1 gene activation and repression in monocytic cells and keratinocytes. Using induced d2eGFP expression as a readout for activated immune signaling at the single-cell level, we demonstrate the application of the reporter for FACS-based selection of cells with genotypes supporting cGAS-STING signaling. Our studies provide a novel approach for monitoring on/off-switching of innate immune signaling and form the basis for investigating genotypes affecting immune regulation at the single-cell level.
... Viral interference is a form of resistance that may occur after a host becomes infected with one virus, and prevents infection and replication of a second virus. It has been speculated that upon infection by the first virus, either through the cell-mediated response, or more likely, through the innate immune response, a rapid state of immune activation that protects against simultaneous infections by other viruses is induced causing a temporarily 'antiviral state' [20,[22][23][24]. Several epidemiological studies have supported the occurrence of viral interference as well, in particular during the 2009 influenza pandemic [17][18][19][20]. ...
Article
Influenza-like illness (ILI) can be caused by a range of respiratory viruses. The present study investigates the contribution of influenza and other respiratory viruses, the occurrence of viral co-infections, and the persistence of the viruses after ILI onset in older adults. During the influenza season 2014–2015, 2366 generally healthy community-dwelling older adults (≥60 years) were enrolled in the study. Viruses were identified by multiplex ligation–dependent probe-amplification assay in naso- and oropharyngeal swabs taken during acute ILI phase, and 2 and 8 weeks later. The ILI incidence was 10.7%, which did not differ between vaccinated and unvaccinated older adults; influenza virus was the most frequently detected virus (39.4%). Other viruses with significant contribution were: rhinovirus (17.3%), seasonal coronavirus (9.8%), respiratory syncytial virus (6.7%), and human metapneumovirus (6.3%). Co-infections of influenza virus with other viruses were rare. The frequency of ILI cases in older adults in this 2014–2015 season with low vaccine effectiveness was comparable to that of the 2012–2013 season with moderate vaccine efficacy. The low rate of viral co-infections observed, especially for influenza virus, suggests that influenza virus infection reduces the risk of simultaneous infection with other viruses. Viral persistence or viral co-infections did not affect the clinical outcome of ILI.
... IFNs carry out pleiotropic effects through the induction of IFN-stimulated genes (ISGs), which control cellular proliferation, metabolism, Ag presentation, cell recruitment and activation, and inflammation. Across decades of studies, IFNs have irrefutably been deemed essential in the interference against viral infections across tissues, a property that has earned them their name (1). It is now understood that IFNs play a protective role in the pathogenesis of bacterial, fungal, and parasitic infections (26), although in certain contexts, their expression can worsen infectious outcomes (7,8). ...
Article
IFNs are comprised of three families of cytokines that confer protection against pathogen infection and uncontrolled cellular proliferation. The broad role IFNs play in innate and adaptive immune regulation has placed them under heavy scrutiny to position them as "friend" or "foe" across pathologies. Genetic lesions in genes involving IFN synthesis and signaling underscore the disparate outcomes of aberrant IFN signaling. Abrogation of the response leads to susceptibility to microbial infections whereas unabated IFN induction underlies a variety of inflammatory diseases and tumor immune evasion. Type I and III IFNs have overlapping roles in antiviral protection, yet the mechanisms by which they are induced and promote the expression of IFN-stimulated genes and inflammation can distinguish their biological functions. In this review, we examine the molecular factors that shape the shared and distinct roles of type I and III IFNs in immunity.
... Interferon (IFN) was first described in the 1950s as an agent from T cells or NK cells that interferes with viral replication [16]. Signaling from the interferon receptors was subsequently well-characterized [17][18][19]. Janus kinase (JAK) and the signal transducer and activators of transcription (STAT) were found to be the main signaling pathways mediating interferon-induced gene expression [19,20] and resulting in the activation of interferon-stimulated response elements (ISREs) [19,20] and gamma interferon activation sites (GASs) [21,22]. ...
Article
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There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1 promoter, which are as follows: (a) the extrinsic mechanism, which is activated by interferon gamma (IFN γ) by tumor infiltration lymphocytes (TIL) and NK cells; (b) the intrinsic mechanism of EGFR or PTEN loss resulting in the activation of the MAPK and AKT pathways and then stat 1 and 3 activation; and (c) 9p24 amplicon amplification, resulting in PD-L1 and Jak2 activation. We also review the literature and postulate that many of the failures of CPI therapy in MPN are likely due to excessive MDSC activities. We list all of the anti-MDSC agents, especially those with ruxolitinib, IMID compounds, and BTK inhibitors, which may be combined with CPI therapy in the future as part of clinical trials applying CPI therapy to Ph(-) MPN.
... En réponse aux IFNs, des centaines d'ISGs sont exprimés par les cellules infectées afin de limiter la propagation du pathogène (Schneider et al., 2014). Cinq ans après la découverte du rôle antiviral des IFNs en 1957, leurs propriétés antiprolifératives ont été observées (Isaacs Alick et al., 1957;Paucker et al., 1962). Depuis, de nombreuses études ont montré que les IFNs réduisent la prolifération cellulaire, ce qui contribue à limiter la propagation du pathogène, notamment lors d'une infection par un virus oncogénique (Bekisz et al., 2010). ...
Thesis
Le cancer du sein est un problème de santé publique majeur qui tue plus de 600 000 femmes par an dans le monde. La majorité des patientes répondent bien au traitement initial, mais dans de nombreux cas, les cellules cancéreuses développent des mécanismes de résistance au traitement, ce qui conduit à une récidive tumorale fatale pour la patiente. Pour tenter d'élucider les mécanismes de résistance du cancer du sein à la chimiothérapie, le partenaire industriel de cette thèse CIFRE (Xentech) a développé un large panel de PDX (pour Patient Derived Xenograft). Ce modèle expérimental préclinique consiste à implanter, sur des souris immunodéficientes, des fragments de tumeurs directement prélevées chez les patientes. L'analyse de ces PDXs après traitement des souris par chimiothérapie a permis de mettre en évidence la surexpression d'une signature de gènes cibles des interférons (IFN), dénommée signature IFN/STAT1, par les cellules cancéreuses résiduelles, c'est-à-dire les cellules qui ont résisté à la chimiothérapie et qui sont responsables de la récidive tumorale. Le but de ce travail de thèse était i) d'élucider les mécanismes d'induction de cette signature et ii) d'évaluer son impact sur la progression tumorale mammaire. Nous avons d'abord identifié des modèles cellulaires de cancer du sein qui reproduisent in vitro l'induction de cette signature suite à un stress génotoxique (chimiothérapie). Nous avons démontré que cette signature était induite par l'expression d'IFNs qui, par un mécanisme autocrine/paracrine, activent la voie de signalisation canonique JAK/STAT. Nous avons ensuite démontré que cette production d'IFN était induite par la voie STING/TBK1/IRF3. STING (Stimulator of Interferon Genes) est un senseur de l'ADN cytosolique, bien connu pour être activé dans les cellules immunitaires suite à une infection par un pathogène à ADN (virus, bactéries). Nous avons proposé que, dans les cellules cancéreuses, STING est activé par l'ADN génomique endommagé qui s'accumule dans le cytoplasme suite au traitement génotoxique. C'est la première fois que l'activation de la voie STING/TBK1/IRF3 est mise en évidence dans le contexte tumoral humain. Au plan fonctionnel, nous avons démontré que l'expression de la grande majorité des gènes de la signature IFN/STAT1 conférait une résistance au traitement génotoxique. Au cours de ces travaux, nous avons découvert une localisation subcellulaire inattendue de STING. Alors que cette protéine est habituellement décrite comme résidente du réticulum endoplasmique, nous avons détecté sa présence à la membrane interne du noyau des cellules cancéreuses. Cette observation nous a conduit à découvrir que STING stimulait la réparation de l'ADN des cellules cancéreuses, en interagissant avec le complexe nucléaire de réparation DNA-PK, et en stimulant son assemblage aux sites de cassures de l'ADN. Ainsi, l'inhibition génétique de STING augmente la quantité d'ADN endommagé, diminue la viabilité des cellules cancéreuses, et les rend plus sensibles à un traitement génotoxique. Ces travaux révèlent la première fonction de STING indépendante de l'induction de gènes pro-inflammatoires. Au vu de la capacité de STING à stimuler l'immunité anti-tumorale (immunosurveillance), des agonistes de STING sont actuellement testés en essais cliniques dans différents cancers. Allant à l'encontre du dogme actuel, notre travail démontre un rôle pro-tumoral de STING intrinsèque aux cellules cancéreuses, impliquant deux mécanismes : l'expression de gènes de survie et la réparation de l'ADN. Cette découverte dévoile un nouveau paradigme quant à l'implication de STING dans le cancer et pose la question de son ciblage thérapeutique. Alors que la tendance actuelle est à la stimulation, son inhibition pourrait dans certains cas être bénéfique.
... Type I IFN was originally described as a soluble factor, produced by cells treated with inactivated non-replicating viruses, that subsequently successfully blocked or interfered on infection with the live virus (5,6). The rapid induction and amplification of the type I IFN system is a key component of antiviral immunity (e.g., against the novel coronavirus) which activates the JAK-STAT signalling pathway and transcription of IFN-stimulated genes (7). ...
Article
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Aicardi-Goutières syndrome (AGS) is a rare hereditary early-onset encephalopathy. The syndrome was first described in 1984, and is characterised by upregulation of the type I interferon (IFN) pathway, which is involved in the host immune response against viral infections, including SARS-CoV-2. Whilst defects in type I IFN pathways have been described in association with severe coronavirus disease 2019 (COVID-19), less is known about the outcomes of upregulation. We describe an unusual case of generalised panniculitis as a post-COVID-19 phenomenon in a child with AGS. Our patient was initially managed with systemic steroid therapy, but due to relapse of symptoms on weaning, an alternative therapy was sought. In this case, a novel use of ruxolitinib, a JAK inhibitor, has resulted in lasting remission without complications. We discuss the probable protective role of IFN upregulation following COVID-19 infection in AGS and possible immunological mechanisms driving the panniculitis and therapeutic response in our case.
... Deposition of lipopolysaccharide (LPS, an essential component of the outer membrane of Gram-negative bacteria) on the CAM after ES opening was shown to induce a significant inflammatory response that is illustrated by the recruitment of heterophils and monocytes to the immunostimulated site, via the CAM vasculature (Valdes et al., 2002). Following viral infection, the CAM expresses interferon (Isaacs and Lindenmann, 1957). However, data related to the role and the response of the CAM after microbial stimulation are relatively scarce. ...
Article
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The chicken eggshell (ES) consists of 95% calcium carbonate and 3.5% organic matter, and represents the first physical barrier to protect the developing embryo, while preventing water loss. During the second half of development, calcium ions from the inner ES are progressively solubilized to support mineralization of the embryonic skeleton. This process is mediated by the chorioallantoic membrane (CAM), which is an extraembryonic structure that adheres to the eggshell membranes (ESM) lining the inner ES. The CAM surrounds the embryo and all egg contents by day 11 of incubation (Embryonic Incubation Day 11, EID11) and is fully differentiated and functionally active by day 15 of incubation (Embryonic Incubation Day 15, EID15). In this study, we explored the simultaneous morphological modifications in the ES, ESM and the CAM at EID11 and EID15 by scanning electron microscopy. We observed that the tips of the mammillary knobs of the ES remain tightly attached to the ESM fibers, while their bases become progressively eroded and then detached from the bulk ES. Concomitantly, the CAM undergoes major structural changes that include the progressive differentiation of villous cells whose villi extend to reach the ESM and the ES. These structural data are discussed with respect to the importance of ES decalcification in providing the calcium necessary for mineralization of embryo’s skeleton. In parallel, eggshell decalcification and weakening during incubation is likely to impair the ability of the ES to protect the embryo. It is assumed that the CAM could counteract this apparent weakening as an additional layer of physical, cellular and molecular barriers against environmental pressures, including pathogens, dehydration and shocks. However, such hypothesis needs to be further investigated.
... Several cytokines inhibit tumor cell development either directly (anti-proliferative or pro-apoptotic) or indirectly (raising immune cell cytotoxicity against tumor cells). Interferon-alpha (IFN-α), which was identified in 1957 as a result of its antiviral capabilities, is a prime example [142]. Gresser and Bourali [143] reported the anti-tumor effect of IFN-α against several tumor cell lines injected in mice. ...
Article
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A subpopulation of cells in many cancers has stem cell traits, mediates metastasis, and contributes to treatment resistance. These cells are considered as cancer stem cells (CSCs). CSC properties of tumor cells are immensely regulated by close interactions with tumor microenvironment components such as mesenchymal stem cells, tumor related fibroblasts, adipocytes, endothelial cells, and immune cells via the intricate network of cytokines, chemokines, and growth factors. Inflammatory cytokines including interleukin (IL)-1, IL-6, and IL-8 play a major role in these interactions via the activation of signal transduction pathways like Stat3/NF-κB etc. in stromal and tumor cells. The activation of these pathways increases the release of more cytokines, resulting in positive feedback loops which help in CSC self-renewal. The pathways controlled by these cytokine loops are similar to those that are active during chronic inflammation and wound healing, suggesting that they might have critical role in establishing relationship between inflammation and cancer. Anti-inflammatory drugs have been identified to inhibit these cytokines and their receptor mediated pathways. These agents have the potential to target CSCs by inhibiting signals from the tumor microenvironment and considered to be a potential candidate for future therapeutics. The significance of cytokines released from the tumor microenvironment in different phases of cancer, as well as their potential application in cancer therapeutics is discussed in this article.
... Interferon discovered, described as a factor that conferred the property of viral interference [116] , reported by Alick Isaacs and Jean Lindenmann. Its anti-leukemic effect is reported in 1984. ...
Article
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The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period, with multiple anecdotal reports of tumors miraculously disappearing, sometimes spontaneously or after a febrile or infectious episode. Spontaneous tumor regression of untreated malignant tumors is currently a well-accepted albeit rare phenomenon, and it is recognized that immunosuppression is associated with a higher cancer risk. The treatment of bladder carcinoma by intravesical administration of live attenuated Bacillus Calmette-Guérin bacteria was shown to be very effective in 1976 and is now standard treatment. Effective immunity against cancer involves complex interactions between the tumor, the host, and the environment. Cancer immunotherapy uses various strategies to augment tumor immunity and represents a paradigm shift in treating cancer, since attention has become more focused on the “biologic passport” of the individual tumor rather than the site of origin of the tumor. The different types of cancer immunotherapies discussed here include biologic modifiers, such as cytokines and vaccines, adoptive cell therapies, oncolytic viruses, and antibodies against immune checkpoint inhibitors, such as the co-inhibitory T-cell receptor PD-1 and one of its ligands, programmed death-ligand 1.
... Interferons (IFNs) are pleiotropic cytokines that are known as essential players during various types of infections, inflammatory diseases, and tumorigenesis. Since their initial description as molecules interfering with viruses as part of the antiviral host response [1], numerous functions were additionally attributed to them [2,3]. IFNs are not only involved in defence mechanisms during viral infections but also during bacterial infections and infections with other microorganisms. ...
Thesis
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Interferons (IFNs) are manifold cytokines which are involved in the regulation of hundreds of genes regulating several biological processes including cell survival and proliferation, host-response to infection, immune modulation as well as cell death. Previous studies have identified IFNs as key cytokines during gastrointestinal disorders as they influence intestinal epithelial cell death, a hallmark of gastrointestinal inflammation and infection. However, the full scope of IFN-mediated cell death and its implication during gastrointestinal inflammation and infection is not fully understood and requires further molecular and functional investigations. Previous studies revealed Caspase 8 deficient (Casp8ΔIEC) mice as a suitable model to investigate necroptosis in the context of Crohn’s disease like inflammation and gastrointestinal infections. Interestingly, genetic susceptibility was sufficient to drive mild ileal inflammation and Paneth cell death, whereas environmental microbial factors determine location and extent of inflammatory lesions along the whole gastrointestinal tract in Casp8ΔIEC mice [A]. Furthermore, STAT1 transcriptionally regulated necroptosis in the small intestine, but was not involved in intestinal inflammation. In contrast to this, STAT2 contributed to ileitis but not to Paneth cell death and dysfunction in the Caspase-8 deficient background. Moreover, results derived from experimentally induced colitis revealed that colonic tissue destruction and cell death was caused by necroptosis which was independent of STAT1 [C]. Surprisingly, during gastrointestinal infection, STAT1 orchestrated cell death in colonic tissue [D]. In summary, the presented studies provided molecular and functional evidence for a key role of IFN-STAT1 mediated regulated cell death during gastrointestinal inflammation and infection. STAT1 coordinates cell death in the small intestine and contributes to Paneth cell dysfunction, whereas the IFN-STAT1 axis in the colon highly depends on the disease context. Thus, the data derived from this thesis demonstrate that IFN-STAT signalling is located at the crossroad of different regulated cell death pathways and the specific role of STAT1 with distinct functions depending on the cellular and disease context (discussed in [B]).
Article
Interferons (IFN) are immunomodulating, antiviral and antiproliferative cytokines for treatment of multiple indications, including cancer, hepatitis, and autoimmune disease. The first IFNs were discovered in 1957, first approved in 1986, and are nowadays listed in the WHO model list of essential Medicines. Three classes of IFNs are known; IFN–α2a and IFN-β belonging to type-I IFNs, IFN-γ a type-II IFN approved for some hereditary diseases and IFN-λs, which form the newest class of type-III IFNs. IFN-λs were discovered in the last decade with fascinating yet under discovered pharmaceutical potential. This article reviews available IFN drugs, their field and route of application, while also outlining available and future strategies for bioconjugation to further optimize pharmaceutical and clinical performances of all three available IFN classes.
Article
Introduction: Five jakinibs are approved for the treatment of rheumatic diseases. There has been a question of their relative safety to other medications since their approval. Areas covered: A literature search was conducted in Pub Med for the integrated safety databases of these molecules in their clinical trial program, registries, and insurance claims data and in a prospective head-to-head study compared to tumor necrosis factor inhibitors in a high-risk population for cardiovascular and malignancy events. There were no differences found in the safety databases, registries or insurance claims data indicating jakinibs are more likely to cause major adverse cardiac events, malignancy, venous thrombotic episodes, infections, and mortality compared to other medications. The head-to-head trial found there were numerically more of these events with the jakinib compared to tumor necrosis factor inhibitors. Expert opinion: Cardiac events and malignancy occur more frequently in rheumatoid patients with active disease. Although the safety databases, claims data and registries suggest there is no difference in the risks with a jakinib versus biologics, the prospective safety study showed these events occur numerically higher in patients at the highest risk for these events. In this population, one should consider using a biologic before a jakinib.
Article
Interferons (IFNs) are divided into 3 types (type I, type II, and type III) on the basis of sequence homology and functional properties. Recombinant IFNs have been approved by regulatory agencies in many countries for clinical treatment of hepatitis B, hepatitis C, and other diseases; these IFNs are mainly produced in microorganisms and mammalian cell systems. However, there are serious obstacles to the production of recombinant IFNs in microorganism systems; for example, the recombinant IFN may have different glycosylation patterns from the native protein, be present in insoluble inclusion bodies, be contaminated with impurities such as endotoxins and nucleic acids, have a short half-life in human blood, and incur high production costs. Some medicinal proteins have been successfully expressed in plants and used in clinical applications, suggesting that plants may also be a good system for IFN expression. However, there are still many technical problems that need to be addressed before the clinical application of plant-expressed IFNs, such as increasing the amount of recombinant protein expression and ensuring that the IFN is modified with the correct type of glycosylation. In this article, we review the classification of IFNs, their roles in antiviral signal transduction pathways, their clinical applications, and their expression in plant systems.
Article
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Type I interferons (IFNs) have broad and potent antiviral activity. We review the interplay between type I IFNs and SARS-CoV-2. Human cells infected with SARS-CoV-2 in vitro produce low levels of type I IFNs, and SARS-CoV-2 proteins can inhibit various steps in type I IFN production and response. Exogenous type I IFNs inhibit viral growth in vitro. In various animal species infected in vivo, type I IFN deficiencies underlie higher viral loads and more severe disease than in control animals. The early administration of exogenous type I IFNs improves infection control. In humans, inborn errors of, and auto-antibodies against type I IFNs underlie life-threatening COVID-19 pneumonia. Overall, type I IFNs are essential for host defense against SARS-CoV-2 in individual cells and whole organisms.
Chapter
Dawn of the twenty-first century has seen a concerted focus on bench research that could be translated into therapeutic interventions in hitherto blinding eye diseases that either did not have any treatment or had at best a very limited successful outcome. This focused approach in laboratory research, aided largely by an exponential growth in the biotechnology tools, has led to a better understanding of the highly complex cell biology and the pathophysiological disease pathways and the discovery of the potential therapeutic targets for interventions. Inherited retinal disorders, the commonest example of which the retinitis pigmentosa affects millions of patients worldwide, have its onset in early childhood and make the affected blind in the prime of youth. Discovery of the affected genes and extensive research for safe and effective vectors for gene transfer led to among the first FDA-approved gene therapy with Luxturna and the beneficial results sustainable up to 4 years of the follow-up currently available. For the patients who do not have any viable photoreceptors or have a polygenic disease, a breakthrough has been achieved in optogenetics with the successful expression of an opsin gene in bipolar cells of the retina which are the second downstream neuron in the visual pathways. The initial results of its successful use in humans were reported recently. Several controlled clinical trials are underway for gene therapy in age-related macular degeneration which affects nearly 200 million people in the world both for the dry and the wet or neovascular degeneration (nAMD). Discovery of the vascular endothelial growth factor (VEGF) in 1989 and development of its antibodies soon after have led to a revolutionary change in the management of blinding retinal diseases like nAMD, diabetic macular oedema, proliferative diabetic retinopathy and the retinal vascular occlusions. The standard of care has shifted from the destructive laser photocoagulation to the use of intraocular injections, currently the most frequent interventional procedure performed among all the procedures done for the human diseases across the spectrum. Glaucoma is another focus of translational research and is now recognized as a neurodegenerative disorder. Several strategies are being tested to treat it with a variety of neurotrophic factors. Cell-based therapies have seen the first human photoreceptor transplant in Japan from a donor 3-D retina organoid grown in the lab. Human embryonic stem cells are being tested in several clinical trials to repopulate the retinal pigment epithelial layer, one of the most vital layers that sustain photoreceptors. Discovery of the polymerase chain reaction to generate billions of copies of DNA not only revolutionized the field of cell biology but also provided a highly sensitive tool to diagnose intraocular infections with hitherto difficult to diagnose fastidious organisms that cause ocular infections. Exponential growth in the understanding of the inflammatory pathways has found new targets for the treatment of inflammatory eye diseases with safe and effective biological antibodies that are being increasingly used in the clinics all over the world to save patients from going blind.
Chapter
Immunology of ducks, geese, turkeys, and quail has progressed due to the agricultural importance of these birds and the need for effective vaccines. Recent availability of avian genomes and transcriptomes has facilitated discovery of immune genes. However, progress in gene function and cellular immune processes lags due to time and effort required to generate the species-specific reagents necesary. Here, we update a compilation of reagents and tools with recent progress in immunology of agricultural species. Many duck and turkey interferons, cytokines, and chemokines have been identified by homology to chicken genes, despite significant evolutionary divergence. Duck and turkey pattern recognition receptors have been characterized in efforts to understand pathogen susceptibility. The major histocompatibility complexes (MHCs) of duck and quail reveal elaboration, while MHC of turkey is compact similar to that of chicken. Some monoclonal antibodies (MAbs) to chicken surface antigens cross-react with turkey and quail, but very few with duck cells. MAbs to duck CD4, CD8, and IgL allow separation of duck leukocyte subsets. However, paucity of cell lines for these species remains a major hurdle.
Chapter
Cytokines act through their membrane-bound receptors to transmit a variety of signals including cell survival, proliferation, differentiation and functional activity. Cytokine receptors are a conserved family of about 40 members that includes the receptors for hormones, interleukins, interferons and colony stimulating factors. Abnormal cytokine levels or aberrations in their signaling pathways can lead to a variety of diseases including cancers and inflammatory conditions reflecting their importance in normal hematopoiesis and immunity. Determination of the three-dimensional atomic structures of cytokines and their receptors has provided detailed insights into how cytokines transmit biological signals across cell membranes.
Article
The discovery that genetic variation within the interferon lambda locus has a profound effect on the outcome of hepatitis C virus (HCV) treatment and spontaneous clearance of HCV is one of the great triumphs of genomic medicine. Subsequently, the IFNL4 gene was discovered and proposed as the causal gene underlying this association. However, there has been a lively debate within the field concerning the causality, which has been further complicated by a change in naming. This review summarizes the genetic data available for the IFNL3/IFNl4 loci and provides an in-depth discussion of causality. We also discuss a new series of interesting data suggesting that the genetic variation at the IFNL4 loci influences the evolution of the HCV virus and the implication this relationship between our genetic makeup and virus evolution has upon our understanding of the IFNL4 system. Finally, new data support an influence of the IFNL4 gene upon liver inflammation and fibrosis that is independent of etiology, thereby linking the IFNL4 gene to some of the major liver diseases of today.
Article
Cytokines are soluble factors vital for mammalian physiology. Cytokines elicit highly pleiotropic activities, characterized by their ability to induce a wide spectrum of functional responses in a diverse range of cell subsets, which makes their study very challenging. Cytokines activate signalling via receptor dimerization/oligomerization, triggering activation of the JAK (Janus kinase)/STAT (Signal Transducer and activator of transcription) signalling pathway. Given the strong crosstalk and shared usage of key components of cytokine signalling pathways, a long‐standing question in the field pertains to how functional diversity is achieved by cytokines. Here, we discuss how biophysical – e.g. ligand‐receptor binding affinity and topology – and cellular – e.g. receptor, JAK and STAT protein levels, endosomal compartment – parameters contribute to the modulation and diversification of cytokine responses. We review how these parameters ultimately converge into a common mechanism to fine‐tune cytokine signalling that involves the control of the number of Tyr residues phosphorylated in the receptor intracellular domain upon cytokine stimulation. This results in different kinetics of STAT activation, and induction of specific gene expression programs, ensuring the generation of functional diversity by cytokines using a limited set of signalling intermediaries. We describe how these first principles of cytokine signalling have been exploited using protein engineering to design cytokine variants with more specific and less toxic responses for immuno‐therapy.
Chapter
It has been noted that interferon can exert an antiproliferative effect by stimulating cells of the immune system. Interferon has been shown to be effective in the treatment of chronic myeloproliferative neoplasms. Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. Studies have been showing the effectiveness of interferon alpha in reducing the number of platelets in essential thrombocythemia, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Additionally, it turned out to be effective in reducing the size of the spleen. Interferon has also been shown to be effective in inducing long-term molecular remissions. The introduction of new forms of interferon such as ropeginterferon and the combination of interferon alpha with newly introduced drugs from other groups causes that interferon remains an important drug in the field of chronic myeloproliferative disorders. The chapter presents the results of clinical trials and the experiences of various centers in its usage for mieloproliferative neoplasms.
Article
Type I interferon (IFN-I) mediates tissue damage in a wide range of kidney disorders, directly affecting the biology and function of several renal cell types including podocytes, mesangial, endothelial and parietal epithelial cells (PECs).Enhanced IFN-I signalling is observed in the context of viral infections, autoimmunity (e.g., systemic lupus erythematosus, SLE), and the type 1 interferonopathies (T1Is), rare monogenic disorders characterised by constitutive activation of the IFN-I pathway. All of these IFN I-related disorders can cause renal dysfunction, and share pathogenic and histopathological features. Collapsing glomerulopathy, a histopathological lesion characterised by podocyte loss, collapse of the vascular tuft and PEC proliferation, is commonly associated with viral infections, has been described in T1Is such as Aicardi-Goutières syndrome and STING-associated vasculopathy with onset in infancy (SAVI), and can also be induced by recombinant IFN-therapy. In all of these conditions, podocytes and PECs seem to be the primary target of IFN I-mediated damage. Additionally, immune-mediated glomerular injury is common to viral infections, SLE, and T1Is such as COPA syndrome and DNASE1L3 deficiency, diseases in which IFN-I apparently promotes immune-mediated kidney injury. Finally, kidney pathology primarily characterised by vascular lesions (e.g., thrombotic microangiopathy, vasculitis) is a hallmark of the T1I ADA2 deficiency as well as of SLE, viral infections and IFN-therapy.Defining the nosology, pathogenic mechanisms and histopathological patterns of IFN I-related kidney disorders has diagnostic and therapeutic implications, especially considering the likely near-term availability of novel drugs targeting the IFN-I pathway.
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The innate immune system, the primary defense mechanism of higher organisms against pathogens including viruses, senses pathogen-associated molecular patterns (PAMPs). In response to PAMPs, interferons (IFNs) are produced, allowing the host to react swiftly to viral infection. In turn the expression of IFN-stimulated genes (ISGs) is induced. Their products disseminate the antiviral response. Among the ISGs conserved in many species are those encoding mono-ADP-ribosyltransferases (mono-ARTs). This prompts the question whether, and if so how, mono-ADP-ribosylation affects viral propagation. Emerging evidence demonstrates that some mono-ADP-ribosyltransferases function as PAMP receptors and modify both host and viral proteins relevant for viral replication. Support for mono-ADP-ribosylation in virus–host interaction stems from the findings that some viruses encode mono-ADP-ribosylhydrolases, which antagonize cellular mono-ARTs. We summarize and discuss the evidence linking mono-ADP-ribosylation and the enzymes relevant to catalyze this reversible modification with the innate immune response as part of the arms race between host and viruses.
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Avian viruses of economic interest are a significant burden on the poultry industry, affecting production traits and resulting in mortality. Furthermore, the zoonosis of avian viruses risks pandemics developing in humans. Vaccination is the most common method of controlling viruses; however current vaccines often lack cross‐protection against multiple strains of each virus. The mutagenicity of these viruses has also led to virulent strains emerging that can overcome the protection offered by vaccines. Breeding chickens with a more robust innate immune response may help in tackling current and emerging viruses. Understanding the genetic evolution of different lines will thus provide a useful tool in helping the host in the fight against pathogens. This study focuses on the interferon genes and their receptors in different chicken lines that are known to be more resistant or susceptible to particular avian viruses. Comparing genotypic differences in these core immune genes between the chicken lines may explain the phenotypic differences observed and aid the identification of causative variations. The relative resistance/susceptibility of each line to viruses of interest (Marek’s disease virus, infectious bursal disease, infectious bronchitis virus and avian influenza virus) has previously been determined. Here we identify single nucleotide polymorphisms in interferons and downstream genes. Functional prediction tools were used to identify variants that may be affecting protein structure, mRNA secondary structure or transcription factor and micro‐RNA binding sites. These variants were then considered in the context of the research lines and their distribution between phenotypes. We highlight 60 variants of interest in the interferon pathway genes that may account for susceptibility/resistance to viral pathogens.
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Interferons (IFNs) are a group of cellular proteins with critical roles in the regulation of immune responses in the course of microbial infections. Moreover, expressions of IFNs are dysregulated in autoimmune disorders. IFNs are also a part of immune responses in malignant conditions. The expression of these proteins and activities of related signaling can be influenced by a number of non-coding RNAs. IFN regulatory factors (IRFs) are the most investigated molecules in the field of effects of non-coding RNAs on IFN signaling. These interactions have been best assessed in the context of cancer, revealing the importance of immune function in the pathoetiology of cancer. In addition, IFN-related non-coding RNAs may contribute to the pathogenesis of neuropsychiatric conditions, systemic sclerosis, Newcastle disease, Sjögren’s syndrome, traumatic brain injury, lupus nephritis, systemic lupus erythematosus, diabetes mellitus, and myocardial ischemia/reperfusion injury. In the current review, we describe the role of microRNAs and long non-coding RNAs in the regulation of IFN signaling.
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Aims The potential signaling pathways and core genes in ulcerative colitis (UC) were investigated in this study. Furthermore, potential mechanisms of BBR in treating UC were also explored. Methods Expression profiling by array of UC patients were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were determined with the differential analysis. The biological functions of DEGs were analyzed through the Database for Annotation, Visualization and Integrated Discovery (DAVID). The Gene Set Enrichment Analysis (GSEA) was applied to analyze the expression differences between two different phenotype sample sets. Dextran sulfate sodium (DSS) was applied to establish UC model of mice and lipopolysaccharide (LPS) was utilized to induce inflammatory damage of NCM460 cells. Therapeutic effects of berberine (BBR) on disease performance, pathologic changes and serum supernatant indices were analyzed in vivo. To further investigate the potential mechanisms of BBR in treating UC, the expression of genes and proteins in vivo and in vitro were examined by RT-qPCR, immunohistochemical staining and western blotting. Results Immune-inflammatory genes were identified and up-regulated significantly in UC patients. In addition, IFN-γ signaling pathway and its core genes were significantly up-regulated in the phenotype of UC. All disease performance and the pathologic changes of UC in mice were evidently ameliorated by BBR treatment. The pro-inflammatory cytokines of serum, including CXCL9, CXCL1, IL-17 and TNF-α, in UC mice were significantly reduced by treatment of BBR. In terms of mechanisms of BBR in treating UC, the pro-inflammatory and immune-related genes, encoding IFN-γ, IRF8, NF-κB and TNF-α decreased significantly in UC mice followed by BBR treatment. Meanwhile, the expression of IFN-γ and its initiated targets, including IRF8, Ifit1, Ifit3, IRF1, were suppressed significantly by BBR treatment in vivo. The blocking of IFN-γ in vitro led to the silence of IFN-γ signaling pathway after exposure to BBR. Furthermore, the blocking of IFN-γ in vitro led to the silence of IFN-γ signaling pathway after exposure to BBR. Conclusion BBR holds anti-inflammatory activity and can treat UC effectively. The anti-inflammatory property of BBR is tightly related to the suppression of IFN-γ signaling pathway, which is crucial in immune-inflammatory responses of the colon mucosa.
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