SARS-CoV-2, a novel coronavirus (CoV) that causes COVID-19, has recently emerged causing an ongoing outbreak of viral pneumonia around the world. While distinct from SARS-CoV, both group 2B CoVs ...share similar genome organization, origins to bat CoVs, and an arsenal of immune antagonists. In this report, we evaluate type I interferon (IFN-I) sensitivity of SARS-CoV-2 relative to the original SARS-CoV. Our results indicate that while SARS-CoV-2 maintains similar viral replication to SARS-CoV, the novel CoV is much more sensitive to IFN-I. In Vero E6 and in Calu3 cells, SARS-CoV-2 is substantially attenuated in the context of IFN-I pretreatment, whereas SARS-CoV is not. In line with these findings, SARS-CoV-2 fails to counteract phosphorylation of STAT1 and expression of ISG proteins, while SARS-CoV is able to suppress both. Comparing SARS-CoV-2 and influenza A virus in human airway epithelial cultures, we observe the absence of IFN-I stimulation by SARS-CoV-2 alone but detect the failure to counteract STAT1 phosphorylation upon IFN-I pretreatment, resulting in near ablation of SARS-CoV-2 infection. Next, we evaluated IFN-I treatment postinfection and found that SARS-CoV-2 was sensitive even after establishing infection. Finally, we examined homology between SARS-CoV and SARS-CoV-2 in viral proteins shown to be interferon antagonists. The absence of an equivalent open reading frame 3b (ORF3b) and genetic differences versus ORF6 suggest that the two key IFN-I antagonists may not maintain equivalent function in SARS-CoV-2. Together, the results identify key differences in susceptibility to IFN-I responses between SARS-CoV and SARS-CoV-2 that may help inform disease progression, treatment options, and animal model development.
With the ongoing outbreak of COVID-19, differences between SARS-CoV-2 and the original SARS-CoV could be leveraged to inform disease progression and eventual treatment options. In addition, these findings could have key implications for animal model development as well as further research into how SARS-CoV-2 modulates the type I IFN response early during infection.
Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) ...complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.
Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly ...associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognized at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted.
To explore the role of type I IFN in PAH.
Cells were cultured using standard approaches. Cytokines were measured by ELISA. Gene and protein expression were measured using reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knockout (IFNAR1(-/-)) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II, and III IFN levels were elevated in serum of patients with systemic sclerosis associated PAH. Serum interferon γ inducible protein 10 (IP10; CXCL10) and endothelin 1 were raised and strongly correlated together. IP10 correlated positively with pulmonary hemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1(-/-) mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum endothelin 1 levels.
These data indicate that type I IFN, via an action of IFNAR1, mediates PAH.
Interferon α (IFNα) is a cytokine whose production is increased endogenously in response to viral infection and in autoimmune diseases such as systemic lupus erythematosus (SLE). An elevated IFNα ...signature has been associated with clinically observed neuro-behavioural deficits such as mild cognitive impairment, fatigue, depression and psychosis in these diseases. However, the mechanisms underlying these neuropsychiatric symptoms remain largely unknown, and it is as yet unclear how IFNα signalling might influence central nervous system (CNS) function. Aberrant microglia-mediated synaptic pruning and function has recently been implicated in several neurodegenerative and neuropsychiatric diseases, but whether and how IFNα modulates these functions are not well defined.
Using a model of peripheral IFNα administration, we investigated gene expression changes due to IFNAR signalling in microglia. Bulk RNA sequencing on sorted microglia from wild type and microglia-specific Ifnar1 conditional knockout mice was performed to evaluate IFNα and IFNAR signalling-dependent changes in gene expression. Furthermore, the effects of IFNα on microglia morphology and synapse engulfment were assessed, via immunohistochemistry and flow cytometry.
We found that IFNα exposure through the periphery induces a unique gene signature in microglia that includes the expected upregulation of multiple interferon-stimulated genes (ISGs), as well as the complement component C4b. We additionally characterized several IFNα-dependent changes in microglial phenotype, including expression of CD45 and CD68, cellular morphology and presynaptic engulfment, that reveal subtle brain region-specific differences. Finally, by specifically knocking down expression of IFNAR1 on microglia, we show that these changes are largely attributable to direct IFNAR signalling on microglia and not from indirect signalling effects through other CNS parenchymal cell types which are capable of IFNα-IFNAR signal transduction.
Peripheral IFNα induces unique genetic and phenotypic changes in microglia that are largely dependent on direct signalling through microglial IFNAR. The IFNα-induced upregulation of C4b could play important roles in the context of aberrant synaptic pruning in neuropsychiatric disease.
Type I interferons (IFN-1) are cytokines that affect the expression of thousands of genes, resulting in profound cellular changes. IFN-1 activates the cell by dimerizing its two-receptor chains, ...IFNAR1 and IFNAR2, which are expressed on all nucleated cells. Despite a similar mode of binding, the different IFN-1s activate a spectrum of activities. The causes for differential activation may stem from differences in IFN-1-binding affinity, duration of binding, number of surface receptors, induction of feedbacks, and cell type-specific variations. All together these will alter the signal that is transmitted from the extracellular domain inward. The intracellular domain binds, directly or indirectly, different effector proteins that transmit signals. The composition of effector molecules deviates between different cell types and tissues, inserting an additional level of complexity to the system. Moreover, IFN-1s do not act on their own, and clearly there is much cross-talk between the activated effector molecules by IFN-1 and other cytokines. The outcome generated by all of these factors (processing step) is an observed phenotype, which can be the transformation of the cell to an antiviral state, differentiation of the cell to a specific immune cell, senescence, apoptosis, and many more. IFN-1 activities can be divided into robust and tunable. Antiviral activity, which is stimulated by minute amounts of IFN-1 and is common to all cells, is termed robust. The other activities, which we term tunable, are cell type-specific and often require more stringent modes of activation. In this review, I summarize the current knowledge on the mode of activation and processing that is initiated by IFN-1, in perspective of the resulting phenotypes.
T follicular helper (Tfh) cells represent a recently defined CD4
+ T cell subset characterized by the expression of the chemokine receptor CXCR5 and an enhanced ability to support B cells to mount ...antibody responses. Here, we demonstrate that lymph-node-resident CXCR5
+ Tfh cells and gut-homing integrin α
4β
7-expressing T helper cells are generated as separate subsets in the gut-draining mesenteric lymph nodes. Type I interferon signaling in dendritic cells and in nonhematopoietic cells selectively stimulates Tfh cell development in response to antigen in conjunction with Toll-like receptor (TLR)3 or TLR4 agonists. Consistent with this, the ability of dendritic cells to produce the cytokine IL-6, required for in vivo Tfh differentiation, and antibody affinity maturation are both reduced in absence of type I interferon signaling. Thus, our results identify type I interferon as a natural adjuvant that selectively supports the generation of lymph node resident Tfh cells.
Type I interferons (IFN) including IFNα and IFNβ are critical for the cellular defense against viruses. Here we report that increased levels of IFNβ were found in testes from mice deficient in ...MOV10L1, a germ cell-specific RNA helicase that plays a key role in limiting the propagation of retrotransposons including Long Interspersed Element-1 (LINE-1). Additional experiments revealed that activation of LINE-1 retrotransposons increases the expression of IFNβ and of IFN-stimulated genes. Conversely, pretreatment of cells with IFN suppressed the replication of LINE-1. Furthermore, the efficacy of LINE-1 replication was increased in isogenic cell lines harboring inactivating mutations in diverse elements of the IFN signaling pathway. Knockdown of the IFN receptor chain IFNAR1 also stimulated LINE-1 propagation in vitro. Finally, a greater accumulation of LINE-1 was found in mice that lack IFNAR1 compared with wild type mice. We propose that LINE-1-induced IFN plays an important role in restricting LINE-1 propagation and discuss the putative role of IFN in preserving the genome stability.
Background: Type 1 interferons (IFN1) mediate defense against viruses but their role in regulating retrotransposon activities is unknown.
Results: LINE-1 retrotransposon induces IFN1, which in turn inhibits LINE-1 retrotransposition.
Conclusion: IFN1 regulate activities and propagation of LINE-1.
Significance: Given that retrotransposons alter the genome, IFN1 play a role in maintenance of genomic integrity.
Cytokines in clinical cancer immunotherapy Berraondo, Pedro; Sanmamed, Miguel F; Ochoa, María C ...
British journal of cancer,
01/2019, Letnik:
120, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical ...research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials.
Type I interferons (IFNs) are a family of cytokines that represent a first line of defense against virus infections. The 12 different IFN-α subtypes share a receptor on target cells and trigger ...similar signaling cascades. Several studies have collectively shown that this apparent redundancy conceals qualitatively different responses induced by individual subtypes, which display different efficacies of inhibition of HIV replication. Some studies, however, provided evidence that the disparities are quantitative rather than qualitative. Since RNA expression analyses show a large but incomplete overlap of the genes induced, they may support both models. To explore if the IFN-α subtypes induce functionally relevant different anti-HIV activities, we have compared the efficacies of inhibition of all 12 subtypes on HIV spread and on specific steps of the viral replication cycle, including viral entry, reverse transcription, protein synthesis, and virus release. Finding different hierarchies of inhibition would validate the induction of qualitatively different responses. We found that while most subtypes similarly inhibit virus entry, they display distinctive potencies on other early steps of HIV replication. In addition, only some subtypes were able to target effectively the late steps. The extent of induction of known anti-HIV factors helps to explain some, but not all differences observed, confirming the participation of additional IFN-induced anti-HIV effectors. Our findings support the notion that different IFN-α subtypes can induce the expression of qualitatively different antiviral activities.
The initial response against viruses relies in large part on type I interferons, which include 12 subtypes of IFN-α. These cytokines bind to a common receptor on the cell surface and trigger the expression of incompletely overlapping sets of genes. Whether the anti-HIV responses induced by IFN-α subtypes differ in the extent of expression or in the nature of the genes involved remains debated. Also, RNA expression profiles led to opposite conclusions, depending on the importance attributed to the induction of common or distinctive genes. To explore if relevant anti-HIV activities can be differently induced by the IFN-α subtypes, we compared their relative efficacies on specific steps of the replication cycle. We show that the hierarchy of IFN potencies depends on the step analyzed, supporting qualitatively different responses. This work will also prompt the search for novel IFN-induced anti-HIV factors acting on specific steps of the replication cycle.
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