IFN Administration Research Articles

Effect of interferon-α on COVID-19 in-hospital mortality: a large-scale propensity score-matched study.

Coronavirus infection can induce the production of inflammatory cytokines leading to acute respiratory distress syndrome (ARDS) and death. It is well-established that interferons (IFNs) are essential in regulating the immune response, thus their effects of IFNs on COVID-19 patients should be subject to investigation. This study aimed to investigate the effects of IFN-α alone or in combination with remdesivir in hospitalized COVID-19 patients. A multicentre, retrospective study was conducted on COVID-19 patients admitted to three hospitals in Tehran, Iran, from March 20, 2020, to March 18, 2021. The unadjusted and adjusted effects of IFN-α on COVID-19 outcomes were investigated through propensity score matching (PSM) to achieve a 1:1 balanced dataset. Among 4,782 patients, 3,764 were eligible for the study, including 1,704 patients (45.27%) receiving at least one treatment with IFN-α and 2,060 controls not receiving IFN-α. After PSM, 851 IFN-α patients and 851 controls were recruited in the PSM analysis with a median age of 60.8 (standard deviation [SD]: 16.2 and 60.9 [SD: 17.4]), respectively. The PSM results showed no significant difference between the survival curves of the IFN-α group and the control group (p=0.340). However, the unadjusted impact of IFN-α on the risk of mortality was statistically significant (p=0.043, hazard-ratio: 0.86; 95% confidence interval [CI]: 0.75-0.99). Also, the combination of IFN-α and remdesivir had no significant benefit (HR: 89, 95% CI: 0.74-1.34). Our findings indicate that subcutaneous administration of IFN-α, with or without remdesivir, does not have any significant impact on COVID-19 mortality and ICU admission. Future clinical trials considering the time, subtype, and form of IFN-α administration are warranted to investigate the potential therapeutic effects of IFN-α on COVID-19.

IFITM3 regulates fibrinogen endocytosis and platelet reactivity in nonviral sepsis.

Platelets and megakaryocytes are critical players in immune responses. Recent reports suggest infection and inflammation alter the megakaryocyte and platelet transcriptome to induce altered platelet reactivity. We determined whether nonviral sepsis induces differential platelet gene expression and reactivity. Nonviral sepsis upregulated IFN-induced transmembrane protein 3 (IFITM3), an IFN-responsive gene that restricts viral replication. As IFITM3 has been linked to clathrin-mediated endocytosis, we determined whether IFITM3 promoted endocytosis of α-granule proteins. IFN stimulation enhanced fibrinogen endocytosis in megakaryocytes and platelets from Ifitm+/+ mice, but not Ifitm-/- mice. IFITM3 overexpression or deletion in megakaryocytes demonstrated IFITM3 was necessary and sufficient to regulate fibrinogen endocytosis. Mechanistically, IFITM3 interacted with clathrin and αIIb and altered their plasma membrane localization into lipid rafts. In vivo IFN administration increased fibrinogen endocytosis, platelet reactivity, and thrombosis in an IFITM-dependent manner. In contrast, Ifitm-/- mice were completely rescued from IFN-induced platelet hyperreactivity and thrombosis. During murine sepsis, platelets from Ifitm+/+ mice demonstrated increased fibrinogen content and platelet reactivity, which was dependent on IFN-α and IFITMs. Platelets from patients with nonviral sepsis had increases in platelet IFITM3 expression, fibrinogen content, and hyperreactivity. These data identify IFITM3 as a regulator of platelet endocytosis, hyperreactivity, and thrombosis during inflammatory stress.

The Role of the Intestinal Microbiome in Antibiotic Associated Neutropenia

Prolonged antibiotic administration has been associated with bone marrow suppression in approximately 10-15% of patients. The mechanisms that underlie the association between prolonged antibiotic therapy and bone marrow suppression, including neutropenia, remain poorly understood. Our recent studies in murine models demonstrated that prolonged broad-spectrum antibiotics suppress hematopoiesis by depletion of the intestinal microbiota. Furthermore, oral administration of the microbial metabolites nucleotide-binding oligomerization domain-containing protein 1 ligand (NOD1L) and desaminotyrosine (DAT) was sufficient to restore normal hematopoiesis in antibiotic-treated mice. Additionally, Type I IFN signaling in hematopoietic cells was noted to be critical for the intestinal microbiota to promote hematopoiesis, as administration of IFNα during antibiotic therapy rescued normal hematopoiesis. These findings support a paradigm in which products of the intestinal microbiota enter the bloodstream and travel to the bone marrow where they promote the production of growth cytokines that support normal hematopoiesis. To elucidate whether changes in the microbiome similar to those observed in mice also occur in humans treated with prolonged courses of antibiotics, we carried out a multicenter non-treatment, non-intervention study. We enrolled patients aged 0-17 years receiving long-term (>2 weeks) intravenous (IV) or oral (PO) antibiotic courses across two tertiary children's hospitals. We excluded patients with history of abnormal blood counts, bone marrow failure, gastrointestinal infection / syndromes / abnormalities, immunodeficiency, malignancy, severe malnutrition, use of prophylactic antibiotics or use of antibiotics immediately before admission. Patients noted to develop neutropenia while receiving antibiotics were enrolled in the retrospective arm. A stool sample was collected at 2 timepoints: at the start and at the completion of antibiotics for the prospective arm of the study; at the onset of neutropenia while on antibiotics and at resolution of neutropenia after completion of antibiotics for the retrospective arm. Here, we report an interim analysis performed for an initial cohort of 5 patients with antibiotic-associated neutropenia and 10 controls matched for age and race/ethnicity. For clinical data analysis, we assessed continuous variables using parametric and non-parametric tests when appropriate while using χ2 or Fisher's exact tests for categorical variables. Stool samples were sent for 16s rDNA sequencing to determine whether there are significant changes in the composition (individual microbial taxa) and diversity (both alpha and beta) of the gut microbiome between groups; as well as for untargeted metabolomic profiling to assess whether changes in the relative abundance of specific microbiome-related metabolites, including but not limited to NOD1L and DAT, are associated with the development of neutropenia with prolonged antibiotic treatment. Analyses of these data are currently ongoing. Neutropenia occurred in 9.4% of our prospective patient samples (3 out of 32 patients). Median age was 13y (range 6 mo. - 17y) for the neutropenic group and 11y (range 1-15y) for the control group. Forty percent of patients were female in both groups (Table 1). Total length of IV antibiotic and ICU admission were positively correlated with neutropenia in this cohort (Table 2). To our knowledge, this is the first clinical study linking changes in the intestinal microbiota with antibiotic associated neutropenia. The incidence of antibiotic-associated neutropenia was comparable to what has been previously reported. The analysis of stool samples from this cohort through 16sDNA sequencing and untargeted metabolomic profiling will outline specific changes in microbiome load, diversity, as well as specific taxa and metabolites potentially related to the development of neutropenia. Altogether, we hope to utilize an improved understanding of the molecular pathways, mediators and receptors by which the microbiome sustains normal hematopoiesis to prevent and treat antibiotic-associated bone marrow suppression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The m6A demethylase ALKBH5 promotes tumor progression by inhibiting RIG-I expression and interferon alpha production through the IKK\u03b5/TBK1/IRF3 pathway in head and neck squamous cell carcinoma

BackgroundN6-methyladenosine (m6A) RNA modification plays a critical role in various physiological and pathological conditions. However, the role of m6A modification in head and neck squamous cell carcinoma (HNSCC) remains elusive.MethodsIn this study, the expression of m6A demethylases was detected by HNSCC tissue microarray. m6A-RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing were used to identify downstream targets of ALKBH5. Comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) was used to explore the m6A “readers”. Tumor-infiltrating lymphocytes were analyzed in SCC7-bearing xenografts in C3H mice.ResultsHere, we demonstrate the downregulation of m6A status and upregulation of two demethylases in HNSCC. Silencing the m6A demethylase alkB homolog 5, RNA demethylase (ALKBH5) suppresses tumor progression in vitro and in vivo. m6A-RNA immunoprecipitation sequencing reveals that ALKBH5 downregulates the m6A modification of DDX58 mRNA. Moreover, RIG-I, encoded by the DDX58 mRNA, reverses the protumorigenic characteristics of ALKBH5. ChIRP-MS demonstrates that HNRNPC binds to the m6A sites of DDX58 mRNA to promote its maturation. ALKBH5 overexpression inhibits RIG-I-mediated IFNα secretion through the IKKε/TBK1/IRF3 pathway. The number of tumor-infiltrating lymphocytes in C3H immunocompetent mice is reduced by ALKBH5 overexpression and restored by IFNα administration. Upregulation of AKLBH5 negatively correlates with RIG-I and IFNα expression in HNSCC patients.ConclusionsThese findings unveil a novel mechanism of immune microenvironment regulation mediated by m6A modification through the ALKBH5/RIG-I/IFNα axis, providing a rationale for therapeutically targeting epitranscriptomic modulators in HNSCC.

Effects from Oral Administration of Recombinant Interferon-Alpha on Piglet Daily Care

The administration of interferon has improved the antiviral and immunomodulatory abilities of piglets, which is conductive to the prevention of potential diseases or delay the appearance of clinical symptoms. This study aimed to evaluate the effects from administration of recombinant interferon-alpha (IFN-α) on the daily care of piglets. The results were compared to a Chinese herbal drug that was shown to increase serum interferon levels. In addition, the administration routes of oral administration and intramuscular injection were evaluated. Forty (40) piglets with equal age and weight were randomly divided into four groups: control group (group C, without treatment), group H (treated with compound Chinese herbal), group K (administered orally with recombinant IFN-α, 1500 IU per day per piglet), and group J (administered intramuscularly with IFN-α, 4×106 IU per day per piglet). After the treatment of 15 days, both oral and intramuscular treatment of recombinant IFN-α significantly improved the secretion of IFN-gamma (IFN-γ) ( P < 0.05 ), and the effects of intramuscular pathway were faster. In addition, the expression levels of IFN-stimulated genes (MX1 and ISG15) were significantly enhanced ( P < 0.01 ), independently of IFN-α treatment time and serum IFN-γ level. Different from other studies, compound Chinese herbal showed weaker effects on interferon stimulation in piglets. The results indicated that oral administration of recombinant IFN-α improved interferon-induced response of piglets at both serum and molecular levels, which may be applied for improving autoimmunity of piglets.

Оценка эффективности методов профилактики COVID-19 у беременных

Objective. To assess the effectiveness of different preventive measures for novel coronavirus infection in pregnant women. Patients and Methods. This study included 125 pregnant women hospitalized with moderate to severe laboratory-confirmed SARS-CoV-2 infection between September and November 2021 (the fourth pandemic wave), and 175 pregnant women who were not infected with COVID-19 during the same period. All women in these two groups were comparable for gestational age (II–III trimesters, 24–39 weeks), age (20–40 years), social status, parity, body mass index, and had no known COVID-19 risk factors. Results. Our findings revealed that vaccination 3-5 months before pregnancy (OR = 4.12; 95% CI 1.28–13.27; χ2 = 0.022), inconsistent use and/or non-timely replacement of face masks (OR = 5.71; 95% CI 2.83–11.51) were associated with the increased risk of COVID-19 in the second and third trimesters of gestation. It was showed that systematic (once in the morning at 24–48-hour intervals) intranasal administration of recombinant interferon alpha-2b (IFN-α; Grippferon) as compared with a single application after exposure to COVID-19 reduced the disease incidence rate and there was no evident risk of illness (OR = 0.08; 95% CI 0.05–0.14; 19.2% vs 74,3%, p < 0.001). This can be explained by the fact that women were mostly infected in unpredictable conditions (e.g., 29.2% of pregnant women were infected from family members, 23.9% had unknown source of exposure). The use of umifenovir, not currently authorised for the medication-assisted prevention of COVID-19 in pregnant women, and rectal administration of IFN-α suppositories did not reduce the disease incidence rate. Rectal use of IFN-α suppositories by pregnant women off-label increased the incidence (32.0 vs 15.4%, p = 0.001) and risk of developing novel coronavirus infection (OR = 2.58; 95% CI 1.48–4.50). Conclusion. There is a need to improve awareness among pregnant women about the mandatory and timely vaccination against COVID-19 during pregnancy and the importance of strict adherence to wearing face masks. Increased efforts should be made to monitor and inform pregnant women about the use of only authorised medication-assisted preventive measures of SARS-CoV-2 infection, such as intranasal administration of recombinant IFN α-2b (Grippferon). During the epidemic rise in COVID-19 cases, the systematic intranasal administration of recombinant interferon-based medication Grippferon (once in the morning at 24–48-hour intervals) is recommended for pregnant women. Key words: pregnancy, COVID-19, incidence rate, vaccination, recombinant interferon alpha-2b, Grippferon, prevention

The pathogenic role of IFN-α in thyroiditis mouse models

AimPatients with chronic hepatitis C are frequently treated with interferon (IFN)-α. Autoimmune thyroid disease occurs in 20% ~ 40% of IFN-α-treated patients. In this study, the effects of IFN-α administration on triggering and regulating autoimmune thyroiditis in various animal models were evaluated. Main methodsExogenous IFN-α was given to naive CBA mice, and both thyroglobulin (TG) immunization-induced (CBA) and spontaneous autoimmune thyroiditis (NOD·H-2 h4) models. Thyroid function, and anti-thyroglobulin antibody (ATA) and B-cell-activating factor (BAFF) levels were measured. Alterations in transcriptome profiles were analyzed. Key findingsIn the TG-induced thyroiditis model, IFN-α administration reduced plasma free thyroxine levels but did not alter ATA titers, BAFF levels, or the severity of histological changes. Interestingly, even without changes in thyroid functions, four of eight mice in the IFN-α alone group exhibited thyroiditis compared to the control group. Immunologically, mice in the IFN-α group exhibited profound CD3+ cell infiltration in the thyroid and higher plasma BAFF levels compared to the control group. Meanwhile, pathological and serological alterations after IFN-α administration were not observed in the NOD·H-2 h4 model. An RNA sequencing analysis revealed that immunoregulatory signatures were not excited by IFN-α treatment in naive CBA mice. Meanwhile, innate and adaptive immunity, inflammatory cytokine, chemokine, and cell-killing signaling pathways were all stimulated by IFN-α administration after TG immunization of CBA mice. SignificanceWe confirmed the remarkable effects of IFN-α in both initiating thyroid immunity and modulating thyroid function and immunoregulatory signatures in established autoimmune thyroiditis. We suggest that IFN-α should be administered with caution in clinical settings.

Using quantitative MRI to study brain responses to immune challenge with interferon-α

Inflammatory processes in the Central Nervous System (CNS) have been proposed to mediate the association between peripheral inflammation and the development of psychiatric disorders, but we currently lack sensitive measures of CNS inflammation for human studies in vivo. Here we used quantitative MRI (qMRI) to explore the in vivo central response to a peripheral immune challenge in healthy humans, and we assessed whether changes in quantitative relaxometry MRI parameters were associated with changes in peripheral inflammation.Quantitative relaxation times (T1 & T2) and Proton Density (PD) were measured in n ​= ​6 healthy males (mean age ​= ​30.5 ​± ​6.8 years) in two MRI assessments collected before and 24 ​hours after a subcutaneous injection of the proinflammatory cytokine and immune activator, interferon-alpha (IFN-α). Serum levels of immune markers and markers of blood-brain barrier integrity (S100B) were also measured before and after the injection.Region of interest and histogram-based analyses (optimized for the small sample size) showed a statistically significant increase of both T1 (t(5) ​= ​3.78, p ​= 0.013) and PD (t(5) ​= ​2.91, p ​= ​0.033) parameters in the bilateral hippocampus after IFN-α administration. T1 peak values in bilateral hippocampus were positively correlated with serum Tumour Necrosis Factor-alpha levels at 24 ​h after the injection, when this cytokine peaked (Spearman's rho ​= ​0.67, p ​= ​0.018) and negatively correlated with S100B levels (Spearman's rho ​= ​−0.826, p ​= ​0.001).Our data suggest that peripheral administration of IFN-α produces acute changes in brain qMRI which might indicate a brain immune response. This is supported by the association of such changes with low-grade peripheral inflammation.

Isoformononetin, a dietary isoflavone protects against streptozotocin induced rat model of neuroinflammation through inhibition of NLRP3/ASC/IL-1 axis activation

AimsIsoformononetin (IFN), a methoxyl isoflavone present in most of human dietary supplements. However, being a highly potent antioxidant and anti-inflammatory molecule, its activity against neuronal oxidative stress and neuroinflammation has not been explored till now. The present study was inquested to assess the antioxidant, anti-apoptotic and anti-inflammatory activity of IFN against streptozotocin induced neuroinflammation in different brain regions of rat. Main methodsFour groups of animals were subjected to treatment as control, toxic control (STZ; single intracerebrovascular injection), third group (STZ + IFN; 20 mg/kg p.o.), fourth group (IFN) for 14 days. The different brain regions of rats were evaluated for inflammatory, apoptotic and biochemical antioxidant markers. The brain tissues were further assessed for gene expression, immunohistochemical and western blotting examination for localization of inflammasome cascade expression that plays a pivotal role in neuroinflammation. Key findingsThe modulation in oxidant/antioxidant status after exposure of STZ was significantly balanced after administration of IFN to rats. Further, IFN was also found to be an apoptotic agent as it modulates the apoptotic gene (Bax) and anti-apoptotic gene (BcL2) expression. IFN significantly curtailed the augmented protein expression of NLRP3, NLRP2, ASC, NFκBP65, IL-1β and caspase-1 due to STZ administration in cortex and hippocampus rat brain regions. SignificanceThe aforementioned results proclaim the neuroprotective functioning of IFN against STZ induced inflammation. IFN significantly prevents the neuroinflammation by decreasing the generation of ROS that reduces the activation of NLRP3/ASC/IL-1 axis thereby exerting neuroprotection as evidenced in rat model of STZ induced neuroninflammation.

Intranasal type I interferon treatment is beneficial only when administered before clinical signs onset in the SARS-CoV-2 hamster model.

Impaired type I interferons (IFNs) production or signaling have been associated with severe COVID-19, further promoting the evaluation of recombinant type I IFNs as therapeutics against SARS-CoV-2 infection. In the Syrian hamster model, we show that intranasal administration of IFN-α starting one day pre-infection or one day post-infection limited weight loss and decreased viral lung titers. By contrast, intranasal administration of IFN-α starting at the onset of symptoms three days post-infection had no impact on the clinical course of SARS-CoV-2 infection. Our results provide evidence that early type I IFN treatment is beneficial, while late interventions are ineffective, although not associated with signs of enhanced disease.

Abstract 710: Androgen-deprivation therapy boosts MX1 expression, a silent effector against COVID-19

Abstract Cancer is a risk factor for SARS-CoV-2 infection. Recent reports have shown that prostate cancer (PCa) patients undergoing androgen-deprivation therapies (ADT) were partially protected from COVID-19. The human myxovirus resistance gene 1 (MX1) is expressed in many tissues, including prostate, and we have previously demonstrated its antitumoral activity in PCa. This protein participates in the antiviral response and it is an IFN-stimulated gene (ISGs), especially during influenza virus infection. There are ongoing clinical trials for COVID-19 prevention and/or treatment using type I or III interferons. However, IFN administration could enhance a "cytokine-storm" causing a hyper-inflammatory response and contributing to organ failure. In this work, we performed bioinformatics analyses in a case-control study from SARS-CoV-2 positive (n=403) and negative (n=50) patients. We analyzed the response to infection assessing gene expression profiles in nasopharyngeal swabs of key host cell receptors (ACE2, TMPRSS2, BSG/CD147, CTSB, CTSL, ADAM17) and antiviral proteins (MX1, MX2, NRF2, IRF3, HIF1A, HMOX1).SARS-CoV-2 positive cases had higher ACE2, but lower TMPRSS2, BSG/CD147 and CTSB expression. Patient age negatively affected ACE2 expression. MX1 and MX2 were higher in SARS-CoV-2 positive individuals, and negative trends were observed as patients' age increased. Principal Component Analysis determined that ACE2, MX1, MX2 and BSG/CD147 expressions were able to cluster non-COVID-19 and COVID-19 individuals. Multivariable regression showed that MX1 expression significantly increased for each unit of viral load increment.Given that MX1 was differentially expressed between COVID-19 and non-COVID-19 patients, we evaluated MX1 expression in A549 and Calu3 lung cell lines. MX1 was significantly up-regulated upon infection with SARS-CoV-2.Since ADT reduces SARS-CoV-2 infection incidence, we aim to study MX1 regulation by dihydrotestosterone (DHT). We browsed publicly available ChIP-seq experiments evaluating androgen receptor (AR) binding sites in different PCa cell lines under DHT stimulation. Results indicated enriched AR binding sites on the MX1 sequence. Therefore, we treated LNCaP cells with DHT, observing a significant decrease in MX1 mRNA levels. Accordingly, we observed a significant increase of MX1 gene expression in PCa patients after ADT treatment.In summary, our study findings support differences in ACE2, MX1, MX2 and BSG/CD147 expression between COVID-19 and non-COVID-19 patients; and point out to MX1 as a critical responder in SARS-CoV-2 infection. Furthermore, we demonstrated MX1 modulation by ADT. Taking into consideration the fact that PCa patients that underwent ADT were less prone to present the infection, we propose this gene as an alternative druggable target for COVID-19 patients, especially those with PCa as a previous condition. Citation Format: Juan Antonio Bizzotto, Pablo Sanchis, Sofia Lage-Vickers, Rosario Lavignolle, Agustina Sabater, Mercedes Abbate, Ayelen Toro, Florencia Cascardo, Santiago Olszevicki, Nicolas Anselmino, Estefania Labanca, Emiliano Ortiz, Elba Vazquez, Javier Cotignola, Geraldine Gueron. Androgen-deprivation therapy boosts MX1 expression, a silent effector against COVID-19 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 710.

Interferon signaling suppresses the unfolded protein response and induces cell death in hepatocytes accumulating hepatitis B surface antigen.

Virus infection, such as hepatitis B virus (HBV), occasionally causes endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is counteractive machinery to ER stress, and the failure of UPR to cope with ER stress results in cell death. Mechanisms that regulate the balance between ER stress and UPR are poorly understood. Type 1 and type 2 interferons have been implicated in hepatic flares during chronic HBV infection. Here, we examined the interplay between ER stress, UPR, and IFNs using transgenic mice that express hepatitis B surface antigen (HBsAg) (HBs-Tg mice) and humanized-liver chimeric mice infected with HBV. IFNα causes severe and moderate liver injury in HBs-Tg mice and HBV infected chimeric mice, respectively. The degree of liver injury is directly correlated with HBsAg levels in the liver, and reduction of HBsAg in the transgenic mice alleviates IFNα mediated liver injury. Analyses of total gene expression and UPR biomarkers’ protein expression in the liver revealed that UPR is induced in HBs-Tg mice and HBV infected chimeric mice, indicating that HBsAg accumulation causes ER stress. Notably, IFNα administration transiently suppressed UPR biomarkers before liver injury without affecting intrahepatic HBsAg levels. Furthermore, UPR upregulation by glucose-regulated protein 78 (GRP78) suppression or low dose tunicamycin alleviated IFNα mediated liver injury. These results suggest that IFNα induces ER stress-associated cell death by reducing UPR. IFNγ uses the same mechanism to exert cytotoxicity to HBsAg accumulating hepatocytes. Collectively, our data reveal a previously unknown mechanism of IFN-mediated cell death. This study also identifies UPR as a potential target for regulating ER stress-associated cell death.

Association of Administration of IFN-α With Mortality Among Patients Hospitalized With Coronavirus Disease 2019

Aim: Recent studies on coronavirus disease 2019 (COVID-19) have not offered sufficient clinical evidence to support whether IFN-α can decrease the mortality of patients with COVID-19. Method: In this retrospective study, 103 of 1555 hospitalized COVID-19 patients were treated with IFN-α, and the others matched through propensity score matching. Cox regression model, logistics analysis and Kaplan–Meier statistics depicted the survival curve. Results & conclusion: Single factor analysis demonstrated that fewer deaths occurred in patients treated with IFN-α compared with patients treated without IFN-α (p = 0.000). Logistics analysis showed that patients treated with IFN-α had an all-cause mortality odds ratio = 0.01 (95% CI: 0.001–0.110; p = 0.000). The Cox regression model was utilized to determine an all-cause mortality with a hazard ratio of 0.102 (95% CI: 0.030–0.351; p = 0.000). IFN-α can alleviate disease severity and decrease all-cause mortality, especially in critical patients. IFN-α could effectively treat patients with COVID-19.

Intracerebroventricular Administration of Interferon-Alpha Induced Depressive-Like Behaviors and Neurotransmitter Changes in Rhesus Monkeys.

Interferon-alpha (IFN-α) is a cytokine widely used in the treatment of brain cancers and virus infections with side effects including causing depression. Monoamine neurotransmitter systems have been found playing important roles in peripheral IFN-α-induced depression, but how peripheral IFN-α accesses the central nervous system and contributes to the development of depression is poorly known. This study aimed to develop a non-human primate model using long-term intracerebroventricular (i.c.v.) administration of IFN-α (5 days/week for 6 weeks), to observe the induced depressive-like behaviors and to explore the contributions of monoamine neurotransmitter systems in the development of depression. In monkeys receiving i.c.v. IFN-α administration, anhedonia was observed as decreases of sucrose consumption, along with depressive-like symptoms including increased huddling behavior, decreases of spontaneous and reactive locomotion in home cage, as well as reduced exploration and increased motionless in the open field. Chronic central IFN-α infusion significantly increased the cerebrospinal fluid (CSF) concentrations of noradrenaline (NA), and 3,4-dihydroxyphenylacetic acid (DOPAC), but not 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). These CSF monoamine metabolites showed associations with some specific depression-related behaviors. In conclusion, central IFN-α administration induced anhedonia and depression-related behaviors comparable to the results with peripheral administration, and the development of depression was associated with the dysfunction of monoamine neurotransmitters.

Microglial responses to peripheral type 1 interferon

BackgroundInterferon 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.MethodsUsing 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.ResultsWe 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.ConclusionsPeripheral 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 IFNs: A Blessing in Disguise or Partner in Crime in MERS-CoV-, SARS-CoV-, and SARS-CoV-2-Induced Pathology and Potential Use of Type I IFNs in Synergism with IFN-γ as a Novel Antiviral Approach Against COVID-19.

Since the end of 2019, the emergence of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has accelerated the research on host immune responses toward the coronaviruses. When there is no approved drug or vaccine to use against these culprits, host immunity is the major strategy to fight such infections. Type I interferons are an integral part of the host innate immune system and define one of the first lines of innate immune defense against viral infections. The in vitro antiviral role of type I IFNs against Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV (severe acute respiratory syndrome coronavirus) is well established. Moreover, the involvement of type I IFNs in disease pathology has also been reported. In this study, we have reviewed the protective and the immunopathogenic role of type I IFNs in the pathogenesis of MERS-CoV, SARS-CoV, and SARS-CoV-2. This review will also enlighten the potential implications of type I IFNs for the treatment of COVID-19 when used in combination with IFN-γ.

Local IFNα enhances the anti-tumoral efficacy of systemic anti-PD1 to prevent tumor relapse

BackgroundTumor relapse constitutes a major challenge for anti-tumoral treatments, including immunotherapies. Indeed, most cancer-related deaths occur during the tumor relapse phase.MethodsWe designed a mouse model of tumor relapse in which...

Centrally Acting Angiotensin-Converting Enzyme Inhibitor Suppresses Type I Interferon Responses and Decreases Inflammation in the Periphery and the CNS in Lupus-Prone Mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage. Neuropsychiatric lupus (NPSLE) is one of the most common manifestations of human SLE, often causing depression. Interferon-α (IFNα) is a central mediator in disease pathogenesis. Administration of IFNα to patients with chronic viral infections or cancers causes depressive symptoms. Angiotensin-converting enzyme (ACE) is part of the kallikrein–kinin/renin-angiotensin (KKS/RAS) system that regulates many physiological processes, including inflammation, and brain functions. It is known that ACE degrades bradykinin (BK) into inactive peptides. We have previously shown in an in vitro model of mouse bone-marrow-derived dendritic cells (BMDC) and human peripheral blood mononuclear cells that captopril (a centrally acting ACE inhibitor-ACEi) suppressed Type I IFN responsive gene (IRG) expression. In this report, we used the MRL/lpr lupus-prone mouse model, an established model to study NPSLE, to determine the in vivo effects of captopril on Type I IFN and associated immune responses in the periphery and brain and effects on behavior. Administering captopril to MRL/lpr mice decreased expression of IRGs in brain, spleen and kidney, decreased circulating and tissue IFNα levels, decreased microglial activation (IBA-1 expression) and reduced depressive-like behavior. Serotonin levels that are decreased in depression were increased by captopril treatment. Captopril also reduced autoantibody levels in plasma and immune complex deposition in kidney and brain. Thus, ACEi’s may have potential for therapeutic use for systemic and NPSLE.

Induction of antibody responses in mice immunized intranasally with Type I interferon as adjuvant and synergistic effect of chitosan.

Type I IFNs are a range of host-derived molecules with adjuvant potential; they have been used for many years in the treatment of cancer and viral hepatitis. Therefore, the safety of IFNs for human use has been established. In this study, we evaluated the mucosal adjuvanticity of IFN-β administered intranasally to mice with diphtheria toxoid, and suggested a method to improve its adjuvanticity. When IFN-β alone was used as a mucosal adjuvant, no clear results were obtained. However, simultaneous administration of IFN-β and chitosan resulted in an enhancement of the specific serum immunoglobulin G (IgG) and IgA antibody responses, the mucosal IgA antibody response, and antitoxin titers. Furthermore, the intranasal administration of IFN-α alone resulted in a greater increase in antibody titer than IFN-β, and a synergistic effect with chitosan was also observed. These findings suggest that intranasal administration of chitosan and Type I IFNs may display an effective synergistic mucosal adjuvant activity.

IFN-α-2b induces apoptosis by decreasing cellular cholesterol levels in rat preneoplastic hepatocytes

IFN-α administration to patients has been long discouraged and pushed back by new and apparently better drugs; however the adverse secondary effect, the high costs and the lack of specific action, make these new drugs hard to be used and put IFN-α again in the eye of the researchers. IFN-α-2b was demonstrated to induce apoptosis and modulation of lipid metabolism and the mechanisms are still unknown. Here, we sought to find the link between these features using a model of early stage cancer development. Using in vitro and in vivo approaches, we evaluated apoptosis and lipid metabolism. IFN-α-2b induced changes in hepatic cholesterol mass due to decreased synthesis and increased secretion. Interestingly, the drop in cellular cholesterol levels was necessary for IFN-α-2b to induce apoptosis. Results presented in this paper show the complexity of the action of IFN-α-2b on the early stages of liver cancer development. We show for the first time an interrelationship between cholesterol, apoptosis and IFN-α-2b. This makes clear the need for a reevaluation of IFN-α-2b action in order to develop softer, safer and more bearable derivatives. In this regard, knowing the molecular mechanisms by which IFN-α exerts its cellular actions is of crucial importance, and it is the main condition for therapy success for classical and new malignancies.