Interferon

The current study was designed to determine some immunological and biochemical biomarkers in patients with thalassemia major (TM) and thalassemia intermedia (TI), 20 patients with thalassemia and 20 healthy volunteers as control group. The results have shown a significant increase in WBCs also a significant decrease in neutrophil activity and IFN- in TM and TI groups as compared to controls. The levels of Hb decrease in TM and TI groups as compared to controls, while a significant increase has been observed in platelets count. The results have also revealed a significant elevation in Iron and ferritin in TM and TI groups when compared with controls while Transferrin was decreased in the patients when compare with controls. The liver enzymes (AST and ALT) have shown significantly elevated activities in TM an TI groups.

A 27-year-old woman was maintained in an isolated state for 131 days in Carlsbad Caverns, New Mexico. Her diet was vitamin D-depleted. Determinations on the effects of such isolation on levels and activities of peripheral blood cells that are important for hematological homeostasis and immunological function were carried out. Throughout the duration of the study, the percentage of lymphoid cells that expressed CD3, CD4, CD8, CD19, Leu 8, and other markers remained relatively constant although the absolute numbers of these cells varied. Although the percentage of natural killer (NK) cells did not vary, the activity of these cells did change. NK cell activity became elevated as the isolation study progressed. Production of interferon-gamma (IFN-gamma) in response to mitogen stimulation was higher than expected throughout the isolation periods, but returned to the normal range after termination of the isolation. Red and white cell counts dropped significantly upon entering isolation, but soon returned to normal.

Vaccine-induced COVID-19 variants and its impact on the Unvaccinated by Anthony of Boston. Type 1 interferon response is a major anti-viral defense important for immune activation. It is one of the first innate immune barriers against viruses and provides early defense against viral activity. However, early clearance of viral activity can limit the dynamic of antigen availability and subsequent antibody response needed for the development of more circulating antibodies indicative of strong adaptive immunity. Basically, adequate exposure to the antigen allows the body to produce more antibodies, which would provide protection against later infections by the virus. This exposure becomes limited when the type 1 interferon response acts against the virus. The COVID-19 vaccines thus inhibits the type 1 interferon response so that overall active and adaptive immunity can be more efficient. Theoretically this would increase one's chances of infection, but lower one's chances of serious illness and death. However, in this trade-off of inhibiting the type 1 interferon response, the virus is allowed to live longer, spread amongst the population, and mutate. This ultimately places the unvaccinated at serious risk of deadly infection since the virus has become incrementally resistant to the higher antibody level of the vaccinated, making it all the more stronger against the lower antibody level of the unvaccinated. This essentially leaves the unvaccinated population with no other option but to get vaccinated. Unanimous consensus becomes imperative. The entire population has to either agree to vaccinate or agree not to vaccinate. There could be no in-between. All it would take is a few vaccinated people within a largely unvaccinated population to become infected and set off a much stronger strain of the virus on the unvaccinated. This is likely what happened in India and South America with the Delta and Lambda variants respectively. While vaccinations didn't begin

Breast cancer remains the main cause of cancer-related mortality for women worldwide. Main cause of death is the development of therapy-resistant metastases. Relapses occur with a bimodal temporal distribution, with a first peak at 1-2 years after initial therapy and a second peak 2-3 years later. This discontinuous growth kinetics is consistent with the notion that disseminated cancer cells can remain dormant over a prolonged period of time before resuming growth. How cancer cells enter, sustain and exit dormancy, are unanswered questions with relevance to cancer biology, monitoring and therapy. Investigating mechanisms of breast cancer dormancy remains challenging, as in patients the condition is elusive and experimentally there are only a few models that recapitulate the clinical condition. Thus, developing new models to identify clinically relevant mechanisms and candidate therapeutic targets may open new avenues for novel therapies to induce and prolong dormancy. We have observed that cells surviving chemotherapy can enter a state of immunological dormancy. Using this model, we identified IRF-7/Interferon type I/IFNRA as signaling axis essential for this effect. Here we will review concepts and recent developments in cancer metastasis and dormancy with emphasis on breast cancer, and elaborate strategies to exploit them therapeutically.

In this review, an attempt is made to comprehensively study the effectiveness of probiotics for the prevention and/or treatment of viral infectious diseases, which may be useful to combat the new corona virus. This review will provide an overview of the unique mechanism by which viruses are eliminated through the stimulation of type 1 interferon production by probiotics via the activation of dendritic cells. Till today, there are no specific vaccines or treatments for COVID-19. However, there are many ongoing clinical trials which are evaluating potential agents for treatment. Corona virus disease (COVID-19) is an infectious disease caused by a newly discovered corona virus named as SARS Corona virus-2. The pathophysiology of COVID-19 clearly indicate the sensitivity of SARS CoV-2 to IFN. Reports on treatment of COVID-19 patients with IFN shows positive results. Considering the proven antiviral and immunomodulatory activity of probiotics and ability to stimulate interferon production, it is recommended to use probiotics as the adjunctive therapy for the prophylaxis of COVID-19. The ongoing pandemic has upturned the whole world socially and economically. Although further detailed research is necessary in the future, probiotics are expected to be among the rational adjunctive options for the treatment of Corona viral diseases.

The presented experiments we aimed if: (1) The replication of HSV-type 1 can be inhibited with Propolis, Royal Jelly and RK13 IFN; (2) The difference in the viral sensitivity against Propolis, Royal Jelly and RK13 IFN can be seen in vitro-in vivo; (3) If it is possible to use these substances or their's combinations in clinical praxis.

Stroke is a heterogeneous disease caused by different pathogenic mechanisms. Several candidate genes for stroke have been proposed, but few have been replicated. Matrix metalloproteinases (MMPs) are expressed following stroke. We investigated the association of single nucleotide polymorphisms (SNPs) of the MMP3 gene with stroke in the Korean population. This study included 186 stroke patients [116 ischemic stroke (IS) and 70 intracerebral hemorrhage (ICH)] and 668 age-matched control subjects (267 for IS and 401 for ICH). Three SNPs [rs520540 (Ala362Ala), rs602128 (Asp96Asp), and rs679620 (Lys45Glu)] in the coding region of MMP3 were selected and genotyped by direct sequencing. HelixTree, SNPAnalyzer, SNPStats, and Haploview version 4.2 were used to analyze genetic data. Multiple logistic regression models (codominant, dominant, and recessive models) were conducted to evaluate odds ratio, 95% confidence interval, and P value. Three SNPs in the MMP3 gene were significantly associated with IS (P<0.05). The genotype distribution of 3 SNPs differed between the IS and control subjects. However, there was no association of the SNPs between the ICH and control. In analysis of gender, 3 SNPs were also associated with IS in female group (P<0.05). These SNPs remained significantly associated with IS after the Bonferroni correction for multiple testing (P(c)<0.05). Haplotype analysis revealed that no haplotypes were associated with IS or ICH. Overall, the results of our study demonstrate an association of the MMP3 gene with development of IS, and no association of MMP3 with ICH.

Present study reports an update on the molecular interaction of antiviral drugs with viral and host cell components during hepatitis C virus (HCV) infection. In addition to the traditional therapeutic drug regimen, termed as standard of care, some recent drugs have been added in the existing regimen used for HCV infection. These drugs were categorized as direct-acting antivirals (DAAs) agents and "other agents", with their efficacious impact in the control of HCV infection. They target both viral proteases and host cell receptor proteins/enzymes involved in HCV entry into the cell, replication, and assembly to check their propagation both in situ as well as in cell to cell transmission. Recent studies have reported a significant rise in sustained virological response after the use of these drugs both alone and in combination with pegylated interferon-α (PegIFN-α) plus ribavirin. Recently, DAAs have been reported to be highly effective in eradication of HCV infection, especially liver cirrhosis, reducing but not avoiding the occurrence of liver cancer. Some studies have demonstrated that the presence of resistant HCV variants, arising during viral replication, may be controlled by the new drug regimen. It is important to note here that all these drugs are influenced by viral as well as host factors including basic viral load, HCV genotypes, IFN action, interleukin 28B polymorphism and some liver and metabolic diseases, etc. This is an area with ongoing investigations to explore more antiviral agents that may address new challenges in HCV therapy.

Type I interferons (IFNs) are key cytokines endowed with antiviral and immunomodulatory activities. The human type I IFN family consists of 13 subtypes of IFNa, a single IFNb subtype, plus IFNε, IFNk, and IFNv. Type I IFNs exert their biological activities via interaction with a heterodimeric receptor complex – a cell surface receptor composed of two subunits, namely IFNaR1 and IFNaR2. Ligand binding initiates a transcriptional program that leads to the expression of the IFN-regulated genes (IRGs) responsible for the multifaceted activity of type I IFNs. Optimal outcomes of these cytokines are achieved through regulation of the nature, strength, and duration of IFN production; IFN–receptor interaction; and specific signaling pathways that are modulated in a cell type–specific manner. When virus-infected cells are exposed to IFN, they develop what is known as an 'antiviral state,' regulated by the IRGs, in which the viral life cycle is blocked or impaired. However, viruses have developed an impressive array of tactics to circumvent IFN-mediated antiviral responses. Type I IFNs also induce a broad spectrum of cell activities, including cell proliferation and differentiation, angiogenesis, and immunomodulation, regulated by the release of mediators relevant for the innate and adaptive immune responses. Detailed knowledge about how these pathways are regulated will, in turn, further our understanding of the roles of IFN pathways in the pathogenesis of infectious and inflammatory diseases and cancer.

Psoriasis  is  a  skin  disease  where  various  cytokines  play  a  detrimental  role,  yet  our  understanding  of  the disease  is  still  limited.  TNF  is  a  validated  drug  target  in  psoriasis  and  other  autoimmune  diseases,  but  its use  is  associated  with  side  effects.  Some  paradoxical  side  effects  of  anti-TNF  treatment  are  supposedly associated  with  type  I  IFNs,  which  are  also  implicated  in  the  pathogenesis  of  psoriasis.  Recently,  the  IL-23/IL-17  axis  has  been  associated  with  psoriasis  as  well,  and  new  drugs  targeting  this  axis  have  already been  developed.  Findings  suggest  that  these  cytokines  are  interwoven.  We  discuss  recent  findings reinforcing  the  role  of  TNF,  Type  I  IFNs  and  IL-17  in  the  pathogenesis  of  psoriasis  and  the  apparent inflammatory  interplay  between  these  three  cytokines.

The cytoplasmic retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiate interferon (IFN) production and antiviral gene expression in response to RNA virus infection. Consequently, RLR signalling is tightly regulated by both host and viral factors. Tripartite motif protein 25 (TRIM25) is an E3 ligase that ubiquitinates multiple substrates within the RLR signalling cascade, playing both ubiquitination-dependent and-independent roles in RIG-I-mediated IFN induction. However, additional regulatory roles are emerging. Here, we show a novel interaction between TRIM25 and another protein in the RLR pathway that is essential for type I IFN induction, DEADbox helicase 3X (DDX3X). In vitro assays and knockdown studies reveal that TRIM25 ubiquitinates DDX3X at lysine 55 (K55) and that TRIM25 and DDX3X cooperatively enhance IFNB1 induction following RIG-I activation, but the latter is independent of TRIM25's catalytic activity. Furthermore, we found that the influenza A virus non-structural protein 1 (NS1) disrupts the TRIM25:DDX3X interaction, abrogating both TRIM25-mediated ubiquitination of DDX3X and cooperative activation of the IFNB1 promoter. Thus, our results reveal a new interplay between two RLR-host proteins that cooperatively enhance IFN-β production. We also uncover a new and further mechanism by which influenza A virus NS1 suppresses host antiviral defence.

Vitiligo is an autoimmune disease characterized by depigmented patches and macules. It is associated with many autoimmune diseases, the most common of which is thyroid diseases. The association between Interferon (IFN) therapy and vitiligo is rarely reported in the literature, despite its common usage in many diseases particularly hepatitis C viral infection (HCV). We report four cases of vitiligo that appeared after treating HCV with pegylated IFN.
Keys words: hepatitis, Interferon, ribavirine, induced-vitiligo

Many therapeutic reagents for hepatitis B virus infection have established efficacy in goals such as alanine aminotransferase normalization, hepatitis B virus DNA suppression, HBeAg seroconversion, histological improvement, and reduce disease progression. However, it is not established that the efficacy of these reagents for the long-term survival and prevention of hepatocellular carcinoma although recent meta-analyses have also shown antiviral therapy to be efficacious. This article reviews the current status and innovative new options for antiviral therapy for hepatitis B and also discusses the various mechanisms of action for each drug, the results of clinical studies for each therapy, and the problems yet to be solved with respect to hepatitis B treatment.

Viruses utilize numerous mechanisms to counteract the host's immune response. Interferon production is a major component of the host antiviral response. Many viruses, therefore, produce proteins or RNA molecules that inhibit interferon-induced signal transduction pathways and their associated antiviral effects. Surprisingly, some viruses directly induce expression of interferon-induced genes. SM, an early lytic Epstein-Barr virus (EBV) nuclear protein, was found to specifically increase the expression of several genes (interferon-stimulated genes) that are known to be strongly induced by alpha/beta interferons. SM does not directly stimulate alpha/beta interferon secretion but instead induces STAT1, an intermediate step in the interferon signaling pathway. SM is a posttranscriptional activator of gene expression and increases STAT1 mRNA accumulation, particularly that of the functionally distinct STAT1β splice variant. SM expression in B lymphocytes is associated with decreased ...

Hypoxia-inducible factor-1 (HIF-1) is a dimeric transcriptional complex that has been recognized primarily for its role in the maintenance of oxygen and energy homoeostasis. The HIF-1alpha subunit is O(2) labile and is degraded by the proteasome following prolyl-hydroxylation and ubiquitination in normoxic cells. The present review summarizes evidence that HIF-1 is also involved in immune reactions. Immunomodulatory peptides, including interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), stimulate HIF-1 dependent gene expression even in normoxic cells. Both the hypoxic and the cytokine-induced activation of HIF-1 involve the phosphatidylinositol- 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) signaling pathways. In addition, heat shock proteins (HSP) and other cofactors interact with HIF-1 subunits. HIF-1 increases the transcription of several genes for proteins that promote blood flow and inflammation, including vascular endothelial growth factor (VEGF), heme oxygenase-1, endothelial and inducible nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2). The pharmacologic activation of the HIF-1 complex can be desirable in ischemic and inflammatory disorders. In contrast, HIF-1 blockade may be beneficial to prevent tumor angiogenesis and tumor growth.

Interferon-α (IFN) is widely used in the treatment of certain cancers and viral infections, including hepatitis C (HCV). Unfortunately, depression is a common side effect of IFN therapy, affecting approximately a third of HCV patients receiving IFN therapy. Studies have shown that selective serotonin reuptake inhibitors (SSRIs) can effectively treat IFN-induced depression in only 63–75% of cases. For the remaining percentage, depression often necessitates dose reduction of or discontinuation from IFN therapy. Emerging evidence indicates that IFN may cause depression by affecting brain serotonin. IFN has been shown to increase serotonin reuptake and to decrease serotonin synthesis. We hypothesize that SSRIs are not fully effective because they affect only serotonin reuptake, not serotonin synthesis, and that effective treatment must address both uptake and synthesis. 5-Hydroxytryptophan (5-HTP) effectively increases central nervous system synthesis of serotonin. It is the immediate precursor of serotonin and is widely available as a dietary supplement, which is well absorbed after an oral dose. Several double-blind studies have shown 5-HTP to be effective in the treatment of nondrug-induced depression. We hypothesize that patients who become depressed on IFN will respond to the synergistic combination of SSRIs plus 5-HTP.

COVID-19, which is caused by the SARS-CoV-2, has ravaged the world for the past 2 years. Here, we review the current state of research into the disease with focus on its history, human genetics and genomics and the transition from the pandemic to the endemic phase. We are particularly concerned by the lack of solid information from the initial phases of the pandemic that highlighted the necessity for better preparation to face similar future threats. On the other hand, we are gratified by the progress into human genetic susceptibility investigations and we believe now is the time to explore the transition from the pandemic to the endemic phase. The latter will require worldwide vigilance and cooperation, especially in emerging countries. In the transition to the endemic phase, vaccination rates have lagged and developed countries should assist, as warranted, in bolstering vaccination rates worldwide. We also discuss the current status of vaccines and the outlook for COVID-19.

The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of ...

I geni dell'interferone e COVID-19 Gli interferoni sono molecole ad azione infiammatoria fondamentali per la nostra sopravvivenza. Se non vengono prodotte a sufficienza quando ce n'è bisogno, il sistema immunitario non riesce a difenderci con successo contro patogeni e tumori; nel COVID-19 la produzione di interferoni (soprattutto di quelli di tipo I e di tipo III) è diminuita o ritardata nei soggetti più gravemente colpiti e nei quali si osserva una abnorme risposta infiammatoria Fin dall'inizio della pandemia è apparso subito chiaro che l'infezione da SARS-CoV-2 si presentava con manifestazioni cliniche diverse e molto eterogenee. Tra i positivi al virus, soggetti asintomatici, pazienti affetti da forme lieve, pazienti che hanno necessitato di ricovero ospedaliero e soggetti con forme cliniche gravissime tali da richiedere il ricovero in terapia intensiva.

Filoviruses are highly lethal in humans and nonhuman primates, likely due to potent antagonism of host interferon (IFN) responses early in infection. Filoviral protein VP35 is implicated as the major IFN induction antagonist, while Ebola virus (EBOV) VP24 or Marburg virus (MARV) VP40 are known to block downstream IFN signaling. Despite progress elucidating EBOV and MARV antagonist function, those for most other filoviruses, including Reston (RESTV), Sudan (SUDV), Taï Forest (TAFV), Bundibugyo (BDBV) and Ravn (RAVV) viruses, remain largely neglected. Thus, using standardized vectors and reporter assays, we characterized activities by each IFN antagonist from all known ebolavirus and marburgvirus species side-by-side. We uncover noncanonical suppression of IFN induction by ebolavirus VP24, differing potencies by MARV and RAVV proteins, and intriguingly, weaker antagonism by VP24 of RESTV. These underlying molecular explanations for differential virulence in humans could guide future investigations of more-neglected filoviruses as well as treatment and vaccine studies.

Adherence to treatment is a key to improve cure rates in patients with chronic hepatitis C on interferon-based therapies. We aimed to determine the main reasons for telephone consultations and unscheduled visits in hepatitis C patients under antiviral treatment. Methods: We included all patients with hepatitis C treated with pegylated interferon plus ribavirin who consulted our department by telephone or unscheduled visits. Results: A total of 176 patients (mean age, 48 years; 67.6% male) were under treatment in the inclusion period. We registered 264 phone consultations and 193 unscheduled visits by 109 patients (53% women). The most common reason for telephone consultation was adverse effects (40.2%). The most common actions in response to telephone consultation were providing information (58.3%) and arranging or advancing appointments (22%). Reasons for unscheduled visits included adverse effects (59.1%), errors or administrative queries (13.4%), questions or doubts related to treatment (10.4%), and problems with medication devices (7.7%). Actions in response to unscheduled visits included medical visits (33.7%), training by nurses (24.9%), referral to other specialties (10%), laboratory tests (8.8%), prescription of medication (7.8%), administrative procedures (6.8%), discontinuation of treatment (2.6%), and transfusion (2.1%). Conclusion: Most telephone consultations or unscheduled visits of patients on chronic hepatitis C treatment are related to adverse events.