Role Of IFN-I Research Articles

Beyond antiviral: role of IFN-I in brain development

Interferons and central nervous system resident macrophages, microglia, are well-known for their respective roles in antiviral defense and phagocytosis. Using a classic experimental paradigm for examining activity-dependent neural plasticity, Escoubas, Dorman, et al. recently identified a role for microglial type I interferon signaling in the clearance of unwanted neurons during mouse brain development.

Inflammasome Activation Dampens Type I IFN Signaling to Strengthen Anti-Toxoplasma Immunity.

Innate immunity acts as the first line of defense against pathogen invasion. During Toxoplasma gondii infection, multiple innate immune sensors are activated by invading microbes or pathogen-associated molecular patterns (PAMPs). However, how inflammasome is activated and its regulatory mechanisms during T. gondii infection remain elusive. Here, we showed that the infection of PRU, a lethal type II T. gondii strain, activates inflammasome at the early stage of infection. PRU tachyzoites, RNA and soluble tachyzoite antigen (STAg) mainly triggered the NLRP3 inflammasome, while PRU genomic DNA (gDNA) specially activated the AIM2 inflammasome. Furthermore, mice deficient in AIM2, NLRP3, or caspase-1/11 were more susceptible to T. gondii PRU infection, and the ablation of inflammasome signaling impaired antitoxoplasmosis immune responses by enhancing type I interferon (IFN-I) production. Blockage of IFN-I receptor fulfilled inflammasome-deficient mice competent immune responses as WT mice. Moreover, we have identified that the suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator induced by inflammasome-activated IL-1β signaling and inhibits IFN-I production by targeting interferon regulatory factor 3 (IRF3). In general, our study defines a novel protective role of inflammasome activation during toxoplasmosis and identifies a critical regulatory mechanism of the cross talk between inflammasome and IFN-I signaling for understanding infectious diseases. IMPORTANCE As a key component of innate immunity, inflammasome is critical for host antitoxoplasmosis immunity, but the underlying mechanisms are still elusive. In this study, we found that inflammasome signaling was activated by PAMPs of T. gondii, which generated a protective immunity against T. gondii invasion by suppressing type I interferon (IFN-I) production. Mechanically, inflammasome-coupled IL-1β signaling triggered the expression of negative regulator SOCS1, which bound to IRF3 to inhibit IFN-I production. The role of IFN-I in anti-T. gondii immunity is little studied and controversial, and here we also found IFN-I is harmful to host antitoxoplasmosis immunity by using knockout mice and recombinant proteins. In general, our study identifies a protective role of inflammasomes to the host during T. gondii infection and a novel mechanism by which inflammasome suppresses IFN-I signaling in antitoxoplasmosis immunity, which will likely provide new insights into therapeutic targets for toxoplasmosis and highlight the cross talk between innate immune signaling in infectious diseases prevention.

IFN-I Mediates Lupus Nephritis From the Beginning to Renal Fibrosis.

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) and a major risk factor for morbidity and mortality. The abundant cell-free nucleic (DNA/RNA) in SLE patients, especially dsDNA, is a key substance in the pathogenesis of SLE and LN. The deposition of DNA/RNA-immune complexes (DNA/RNA-ICs) in the glomerulus causes a series of inflammatory reactions that lead to resident renal cell disturbance and eventually renal fibrosis. Cell-free DNA/RNA is the most effective inducer of type I interferons (IFN-I). Resident renal cells (rather than infiltrating immune cells) are the main source of IFN-I in the kidney. IFN-I in turn damages resident renal cells. Not only are resident renal cells victims, but also participants in this immunity war. However, the mechanism for generation of IFN-I in resident renal cells and the pathological mechanism of IFN-I promoting renal fibrosis have not been fully elucidated. This paper reviews the latest epidemiology of LN and its development process, discusses the mechanism for generation of IFN-I in resident renal cells and the role of IFN-I in the pathogenesis of LN, and may open a new perspective for the treatment of LN.

Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment.

A sustained increase in type I interferon (IFN-I) may accompany clinical manifestations and disease activity in systemic autoimmune diseases (SADs). Despite the very frequent presence of IFN-I in SADs, clinical manifestations are extremely varied between and within SADs. The present short review will address the following key questions associated with high IFN-I in SADs in the perspective of precision medicine. 1) What are the mechanisms leading to high IFN-I? 2) What are the predisposing conditions favoring high IFN-I production? 3) What is the role of IFN-I in the development of distinct clinical manifestations within SADs? 4) Would therapeutic strategies targeting IFN-I be helpful in controlling or even preventing SADs? In answering these questions, we will underlie areas of incertitude and the intertwined role of autoantibodies, immune complexes, and neutrophils.

The Roles of Type I Interferon in Co-infections With Parasites and Viruses, Bacteria, or Other Parasites.

Parasites, bacteria, and viruses pose serious threats to public health. Many parasite infections, including infections of protozoa and helminths, can inhibit inflammatory responses and impact disease outcomes caused by viral, bacterial, or other parasitic infections. Type I interferon (IFN-I) has been recognized as an essential immune effector in the host defense against various pathogens. In addition, IFN-I responses induced by co-infections with different pathogens may vary according to the host genetic background, immune status, and pathogen burden. However, there is only limited information on the roles of IFN-I in co-infections with parasites and viruses, bacteria, or other parasites. This review summarizes some recent findings on the roles of IFN-I in co-infections with parasites, including Leishmania spp., Plasmodium spp., Eimeria maxima, Heligmosomoides polygyrus, Brugia malayi, or Schistosoma mansoni, and viruses or bacteria and co-infections with different parasites (such as co-infection with Neospora caninum and Toxoplasma gondii, and co-infection with Plasmodium spp. and H. polygyrus). The potential mechanisms of host responses associated with co-infections, which may provide targets for immune intervention and therapies of the co-infections, are also discussed.

Gravidity-dependent associations between interferon response and birth weight in placental malaria

BackgroundMaternal malarial infection leads to poor perinatal outcomes, including low birth weight from preterm delivery and/or fetal growth restriction, particularly in primigravidas. In placental malaria, Plasmodium falciparum-infected red blood cells cause an inflammatory response that can interfere with maternal–fetal exchange, leading to poor growth. The type I interferon (IFN-I) pathway plays an immunomodulatory role in viral and bacterial infections, usually by suppressing inflammatory responses. However, its role in placental malaria is unknown. This study examines the cytokine responses in placental tissue from subsets of malaria-infected and uninfected women, and attempts to correlate them with particular birth outcomes.Methods40 whole placental biopsy samples were obtained from pregnant women at least 16 years of age recruited to a larger prospective chemoprevention trial against malaria. These were patients at Tororo District Hospital in Uganda, an area of high malaria endemicity where approximately 40% of women have evidence of malaria infection at delivery. They were regularly followed at a local clinic and monitored for fever, with blood smears performed then and at time of delivery to diagnose malaria infection. Placenta biopsies were taken for histological diagnosis of placental malaria, as well as quantitative PCR analysis of genes in the IFN-I pathway (IFN-β, IL-10 and MX-1). Parameters such as infant birth weight and gestational age were also recorded.ResultsHistological analysis revealed placental malaria in 18 samples, while 22 were found to be uninfected. RT-PCR analysis showed a four-fold increase in IFN-β and IL-10 expression in multigravidas with placental malaria when compared to gravidity-matched, uninfected controls. This effect was not observed in primigravidas. Interestingly, linear regression analysis showed a positive association between IFN-β levels and higher birth weights (β = 101.2 g per log2-fold increase in IFN-β expression, p = 0.042). This association was strongest in primigravidas with placental malaria (β = 339.0, p = 0.006).ConclusionsThese results demonstrate differential regulation of the IFN-I pathway in placental malaria according to gravidity, with the greatest anti-inflammatory response seen in multigravidas. The association between IFN-β levels and higher birth weight also suggests a protective role for IFN-I against fetal growth restriction in placental malaria.

IFN-I Independent Antiviral Immune Response to Vesicular Stomatitis Virus Challenge in Mouse Brain.

Type I interferon (IFN-I) plays a pivotal role during viral infection response in the central nervous system (CNS). The IFN-I can orchestrate and regulate most of the innate immune gene expression and myeloid cell dynamics following a noncytopathic virus infection. However, the role of IFN-I in the CNS against viral encephalitis is not entirely clear. Here we have implemented the combination of global differential gene expression profiling followed by bioinformatics analysis to decipher the CNS immune response in the presence and absence of the IFN-I signaling. We observed that vesicular stomatitis virus (VSV) infection induced 281 gene changes in wild-type (WT) mice primarily associated with IFN-I signaling. This was accompanied by an increase in antiviral response through leukocyte vascular patrolling and leukocyte influx along with the expression of potent antiviral factors. Surprisingly, in the absence of the IFN-I signaling (IFNAR−/− mice), a significantly higher (1357) number of genes showed differential expression compared to the WT mice. Critical candidates such as IFN-γ, CCL5, CXCL10, and IRF1, which are responsible for the recruitment of the patrolling leukocytes, are also upregulated in the absence of IFN-I signaling. The computational network analysis suggests the presence of the IFN-I independent pathway that compensates for the lack of IFN-I signaling in the brain. The analysis shows that TNF-α is connected maximally to the networked candidates, thus emerging as a key regulator of gene expression and recruitment of myeloid cells to mount antiviral action. This pathway could potentiate IFN-γ release; thereby, synergistically activating IRF1-dependent ISG expression and antiviral response.

Interferon in the CNS

While the role of interferon during systemic disease is well known and its immune modulating functions and its role in antiviral activity were extensively studied, the role of IFN-I in the brain is less clear. Here we summarize the most important literature on IFN in homeostasis of the CNS and induction of an IFN response during viral infection in the brain. Furthermore, we present work on the roles of IFN in the developing brain as well as during inflammation in the brain. Lastly, we aim to enlighten the functions of IFN on the blood-brain barrier as well as circulation and in cognitive and psychological functions and degeneration. In short, CNS astrocytes produce IFN-β, which is of high relevance for homeostasis in the brain. IFN-β regulates phagocytic removal of myelin debris by microglia. IFN-I limits the permeability of the blood-brain barrier. Disruption of the blood-brain barrier facilitates entrance of peripheral lymphocytes and inflammation. Viral infections during vulnerable phases of embryonic development cause severe fetal pathology and debilitating impairments to human infants. The roles of IFN in these scenarios are diverse and include deficits due to overproduction of IFN during the developmental stage of the brain as seems to be the case in pseudo-TORCH2.

Type I Interferons and Cancer: An Evolving Story Demanding Novel Clinical Applications.

The first report on the antitumor effects of interferon α/β (IFN-I) in mice was published 50 years ago. IFN-α were the first immunotherapeutic drugs approved by the FDA for clinical use in cancer. However, their clinical use occurred at a time when most of their mechanisms of action were still unknown. These cytokines were being used as either conventional cytostatic drugs or non-specific biological response modifiers. Specific biological activities subsequently ascribed to IFN-I were poorly considered for their clinical use. Notably, a lot of the data in humans and mice underlines the importance of endogenous IFN-I, produced by both immune and tumor cells, in the control of tumor growth and in the response to antitumor therapies. While many oncologists consider IFN-I as “dead drugs”, recent studies reveal new mechanisms of action with potential implications in cancer control and immunotherapy response or resistance, suggesting novel rationales for their usage in target and personalized anti-cancer treatments. In this Perspectives Article, we focus on the following aspects: (1) the added value of IFN-I for enhancing the antitumor impact of standard anticancer treatments (chemotherapy and radiotherapy) and new therapeutic approaches, such as check point inhibitors and epigenetic drugs; (2) the role of IFN-I in the control of cancer stem cells growth and its possible implications for the development of novel antitumor therapies; and (3) the role of IFN-I in the development of cancer vaccines and the intriguing therapeutic possibilities offered by in situ delivery of ex vivo IFN-stimulated dendritic cells.

IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes.

Type 1 IFNs (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here, we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration, and impaired MERS-CoV-specific T cell responses. Notably, IFN-I administration within 1 day after infection (before virus titers peak) protected mice from lethal infection, despite a decrease in IFN-stimulated gene (ISG) and inflammatory cytokine gene expression. In contrast, delayed IFN-β treatment failed to effectively inhibit virus replication, increased infiltration and activation of monocytes, macrophages, and neutrophils in the lungs, and enhanced proinflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sublethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-αβ or combination therapy may need to be used cautiously to treat viral infections in clinical settings.

Relative timing of type I interferon response and virus replication determines disease outcome during respiratory virus infection

Abstract Type 1 interferons (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I results in delays in virus clearance and impaired MERS-CoV-specific T cell responses. Administration of IFN-I within 1 day post infection (dpi) protected mice from lethal infection. In marked contrast, delayed IFN-I enhanced the inflammatory response, converting a sublethal to a fatal infection. Together, these results suggest the relative timing of IFN-I signaling and maximal virus replication is key in determining the disease outcome and that IFNab should be used cautiously to treat virus infections.

Murine Cytomegalovirus Disrupts Splenic Dendritic Cell Subsets via Type I Interferon-Dependent and -Independent Mechanisms.

Dendritic cells (DC) are well-known modulators of immunity. This heterogeneous population is composed of defined subsets that exhibit functional specialization and are critical in initiating responses to pathogens. As such, many infectious agents employ strategies to disrupt DC functioning in attempts to evade the immune system. In some instances, this manifests as an outright loss of these cells. Previous work has suggested that, in the absence of an efficient natural killer (NK) cell response, murine cytomegalovirus (MCMV) induces large amounts of interferon (IFN)-I. This heightened IFN-I response is thought to contribute to conventional DC (cDC) loss and delayed development of T cell immunity. However, the precise role of IFN-I in such cDC loss remains unclear. We investigated the effects of licensed NK cells and IFN-I signaling on splenic cDC subsets during MCMV infection and found that a licensed NK cell response partially protects cDC numbers, but does not prevent increases in serum IFN-I. This suggested that high residual IFN-I could contribute to cDC loss. Therefore, we used multiple strategies to modulate IFN-I signaling during MCMV infection including plasmacytoid DC depletion, IFN-I receptor (IFNAR) blockade, and genetic ablation of IFNAR expression. Interestingly, restriction of IFN-I signals did not substantially preserve either CD8+ or CD4+ DC total numbers, but resulted in significant retention and/or accumulation of the splenic CD8− CD4− [double negative (DN)] subset. However, the DN DC effect manifested in a DC-extrinsic manner since IFNAR-deficient cells were not preferentially retained over their IFNAR wild-type counterparts in a mixed-chimera setting. Our results show that IFN-I signaling is not responsible for overt cDC toxicity in the setting of acute MCMV infection and emphasize that additional mechanisms contribute to DC loss and require exploration.

Interdependent and independent roles of type I interferons and IL-6 in innate immune, neuroinflammatory and sickness behaviour responses to systemic poly I:C.

Type I interferons (IFN-I) are expressed in the brain during many inflammatory and neurodegenerative conditions and have multiple effects on CNS function. IFN-I is readily induced in the brain by systemic administration of the viral mimetic, poly I:C (synthetic double-stranded RNA). We hypothesised that IFN-I contributes to systemically administered poly I:C-induced sickness behaviour, metabolic and neuroinflammatory changes. IFN-I receptor 1 deficient mice (IFNAR1(-/-)) displayed significantly attenuated poly I:C-induced hypothermia, hypoactivity and weight loss compared to WT C57BL/6 mice. This amelioration of sickness was associated with equivalent IL-1β and TNF-α responses but much reduced IL-6 responses in plasma, hypothalamus and hippocampus of IFNAR1(-/-) mice. IFN-β injection induced trivial IL-6 production and limited behavioural change and the poly I:C-induced IFN-β response did not preceed, and would not appear to mediate, IL-6 induction. Rather, IFNAR1(-/-) mice lack basal IFN-I activity, have lower STAT1 levels and show significantly lower levels of several inflammatory transcripts, including stat1. Basal IFN-I activity appears to play a facilitatory role in the full expression of the IL-6 response and activation of the tryptophan-kynurenine metabolism pathway. The deficient IL-6 response in IFNAR1(-/-) mice partially explains the observed incomplete sickness behaviour response. Reconstitution of circulating IL-6 revealed that the role of IFNAR in burrowing activity is mediated via IL-6, while IFN-I and IL-6 have additive effects on hypoactivity, but the role of IFN-I in anorexia is independent of IL-6. Hence, we have demonstrated both interdependent and independent roles for IFN-I and IL-6 in systemic inflammation-induced changes in brain function.

Mysteries of type I IFN response: benefits versus detriments.

Mysteries of type I IFN response: benefits versus detriments.

IRF7-dependent type I interferon production induces lethal immune-mediated disease in STAT1 knockout mice infected with lymphocytic choriomeningitis virus.

Following systemic infection with lymphocytic choriomeningitis virus (LCMV), STAT1 knockout (KO) mice but not wild-type, STAT2 KO, IRF9 KO, or IFNAR KO mice develop lethal disease perpetrated by CD4(+) T cells. IRF7 is a key transcriptional activator of type I IFN (IFN-I) during LCMV infection. Here, the role of IRF7 in the lethal host response to LCMV infection in STAT1 KO mice was examined. In contrast to STAT1 KO mice, STAT1/IRF7 double KO (DKO) mice survived LCMV infection with a reduced immune pathology in key organs, such as the liver and spleen. However, similar to STAT1 KO mice, STAT1/IRF7 DKO mice failed to control LCMV replication and spread. LCMV infection in STAT1 KO mice was associated with a significant elevation in the levels of a number of cytokines in serum, including IFN-Is, but this was largely absent in STAT1/IRF7 DKO mice, which had a modest increase in the levels of gamma interferon and CCL2 only. Since IRF7 is known to be a key transcriptional regulator of IFN-I gene expression, the possible role of IFN-I in lethal disease was examined further. STAT1/IFNAR DKO mice, in contrast to STAT1 KO mice, all survived infection with LCMV and exhibited little tissue immune pathology. Additionally, STAT1 KO mice that were deficient for either of the two IFN-I signaling molecules, STAT2 or IRF9, also survived LCMV infection. We conclude that the lethal immune-mediated disease resulting from LCMV infection in STAT1 KO mice is (i) dependent on IRF7-induced IFN-I production and (ii) driven by noncanonical IFN-I signaling via STAT2 and IRF9. Here we report on the basis for the novel, fatal immune-mediated disease of STAT1 KO mice infected with LCMV. Our findings show that, surprisingly, the pathogenesis of this disease is dependent on IRF7-mediated type I interferon production. Moreover, our study identifies noncanonical type I interferon signaling via STAT2 and IRF9 to be essential for the type I IFN-driven fatal disease in LCMV-infected STAT1 KO mice. These results further highlight the significance of noncanonical type I IFN signaling in the pathogenesis of host-mediated injury following viral infection.

Type I interferons suppress CD4+ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

During blood-stage Plasmodium infection, large-scale invasion of RBCs often occurs before the generation of cellular immune responses. In Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice, CD4(+) T cells controlled parasite numbers poorly, instead providing early help to pathogenic CD8(+) T cells. Expression analysis revealed that the transcriptional signature of CD4(+) T cells from PbA-infected mice was dominated by type I IFN (IFN-I) and IFN-γ-signalling pathway-related genes. A role for IFN-I during blood-stage Plasmodium infection had yet to be established. Here, we observed IFN-α protein production in the spleen of PbA-infected C57BL/6 mice over the first 2 days of infection. Mice deficient in IFN-I signalling had reduced parasite burdens, and displayed none of the fatal neurological symptoms associated with PbA infection. IFN-I substantially inhibited CD4(+) T-bet(+) T-cell-derived IFN-γ production, and prevented this emerging Th1 response from controlling parasites. Experiments using BM chimeric mice revealed that IFN-I signalled predominantly via radio-sensitive, haematopoietic cells, but did not suppress CD4(+) T cells via direct signalling to this cell type. Finally, we found that IFN-I suppressed IFN-γ production, and hampered efficient control of parasitaemia in mice infected with non-lethal Plasmodium chabaudi. Thus, we have elucidated a novel regulatory pathway in primary blood-stage Plasmodium infection that suppresses CD4(+) T-cell-mediated parasite control.

Type I Interferon Modulates Monocyte Recruitment and Maturation in Chronic Inflammation

Chronic inflammation is characterized by continuous recruitment and activation of immune cells such as monocytes in response to a persistent stimulus. Production of proinflammatory mediators by monocytes leads to tissue damage and perpetuates the inflammatory response. However, the mechanism(s) responsible for the sustained influx of monocytes in chronic inflammation are not well defined. In chronic peritonitis induced by pristane, the persistent recruitment of Ly6C(hi) inflammatory monocytes into the peritoneum was abolished in type I interferon (IFN-I) receptor-deficient mice but was unaffected by the absence of IFN-gamma, tumor necrosis factor-alpha, interleukin-6, or interleukin-1. IFN-I signaling stimulated the production of chemokines (CCL2, CCL7, and CCL12) that recruited Ly6C(hi) monocytes via interactions with the chemokine receptor CCR2. Interestingly, after 2,6,10,14-tetramethylpentadecane treatment, the rapid turnover of inflammatory monocytes in the inflamed peritoneum was associated with a lack of differentiation into Ly6C(lo) monocytes/macrophages, a more mature subset with enhanced phagocytic capacity. In contrast, Ly6C(hi) monocytes differentiated normally into Ly6C(lo) cells in IFN-I receptor-deficient mice. The effects of IFN-I were specific for monocytes as granulocyte migration was unaffected in the absence of IFN-I signaling. Taken together, our findings reveal a novel role of IFN-I in promoting the recruitment of inflammatory monocytes via the chemokine receptor CCR2. Continuous monocyte recruitment and the lack of terminal differentiation induced by IFN-I may help sustain the chronic inflammatory response.

Type-I interferon modulates monocyte recruitment and maturation in chronic inflammation (94.4)

Abstract Chronic inflammation is characterized by continuous recruitment and activation of immune cells such as monocytes in response to a persistent stimulus. Production of pro-inflammatory mediators by monocytes leads to tissue damage and perpetuates the inflammatory response. However, the mechanism(s) responsible for the sustained influx of monocytes in chronic inflammation are not well defined. In chronic peritonitis induced by 2,6,10,14-tetramethylpentadecane (TMPD; pristane), the persistent recruitment of Ly6Chi inflammatory monocytes into the peritoneum was abolished in type-I interferon (IFN-I) receptor deficient mice but was unaffected by the absence of IFN-γ, TNF-α, IL-6 or IL-1. IFN-I signaling stimulated the production of chemokines (CCL2, CCL7, and CCL12) that recruited Ly6Chi monocytes via interactions with the chemokine receptor CCR2. Interestingly, after TMPD treatment, the rapid turnover of inflammatory monocytes in the inflamed peritoneum was associated with a lack of differentiation into Ly6Clo monocytes/macrophages, a more mature subset with enhanced phagocytic capacity. In contrast, Ly6Chi monocytes/macrophages differentiated normally into Ly6Clo cells in IFN-I receptor deficient mice. The effects of IFN-I were specific for monocytes as granulocyte migration was unaffected in the absence of IFN-I signaling. Taken together, our findings reveal a novel role of IFN-I in promoting the recruitment of inflammatory monocytes via the chemokine receptor CCR2. Continuous monocyte recruitment and the lack of terminal differentiation induced by IFN-I may help sustain the chronic peritoneal inflammatory response.