Interferon Induction Research Articles

Histone deacetylase 3 contributes to the antiviral innate immunity of macrophages by interacting with FOXK1 to regulate STAT1/2 transcription.

It is well known that interferon (IFN)-α/-β activates the JAK/STAT signaling pathway and suppresses viral replication through the induction of IFN stimulated genes (ISGs). Here, we report that knockout of HDAC3 from macrophages results in the decreased expression of STAT1 and STAT2, leading to defective antiviral immunity in cells and mice. Further studies show that HDAC3 interacts with a conserved transcription factor Forkhead Box K1 (FOXK1), co-localizes with FOXK1 at the promoter of STAT1 and STAT2, and is required for protecting FOXK1 from lysosomal system-mediated degradation. FOXK1-deficient macrophages also show low STAT1 and STAT2 expression with defective responses to viruses. Thus, our studies uncover the biological importance of HDAC3 in regulating the antiviral immunity of macrophages through interacting with FOXK1 to regulate the expression of STAT1 and STAT2.

3205 – CANCEROUS IMPACT OF CHRONIC STRESS-HEMATOPOIESIS

Hematopoietic Stem Cells (HSCs) possess the unique attributes of self-renewal and multipotency, which enable the healthy generation of blood and immune cells. HSCs might also be the source of hematologic malignancies. Stress-hematopoiesis, such as infection and inflammation, is suggested to increase the risk of pre-malignancy and leukemia. However, the mechanisms via which stress mediates transformation are unclear, and there is a lack of models with which to interrogate this phenomenon. Revealing how stress-hematopoiesis is skewing HSCs towards malignancy will suggest new ways to modulate the pre-malignant state and minimize the risk of blood cancers. Mice with a mutant p53 allele (R172H, equal to R175H in humans) are challenged by repeated induction of interferons. The protocol includes four weeks of serial injection with pIpC followed by a four-week recovery period, that repeats up to 3 times. Bone-marrow, spleen, thymic, and lymph node cells are stained for lymphoid and myeloid progeny, as well as for stem- and progenitors. FACS cytoflex is used for analysis. Despite clear changes during stimulation, we find little impact of the chronic long-term immune stimulation on most hematological parameters regardless of the status of p53 (wt and mutant p53 allele). However, mice with a mutant p53 allele treated with pIpC exhibited a large spleen, thymus, and lymph nodes. We observed the increased frequencies of CD8+ T cells but not CD4+ T cells in p53MUT mice, following chronic pIpC. In these experiments, p53MUT developed lymphoma while WT did not develop such malignancy during the same time. Our data suggest little direct damage to HSCs by the parameter tested so far, and a profound malignancy in the p53MUT mice following chronic stimulation. Hence, the cancerous impact of stress hematopoiesis might drive malignancy at different levels of the hematopoietic system. Hematopoietic Stem Cells (HSCs) possess the unique attributes of self-renewal and multipotency, which enable the healthy generation of blood and immune cells. HSCs might also be the source of hematologic malignancies. Stress-hematopoiesis, such as infection and inflammation, is suggested to increase the risk of pre-malignancy and leukemia. However, the mechanisms via which stress mediates transformation are unclear, and there is a lack of models with which to interrogate this phenomenon. Revealing how stress-hematopoiesis is skewing HSCs towards malignancy will suggest new ways to modulate the pre-malignant state and minimize the risk of blood cancers. Mice with a mutant p53 allele (R172H, equal to R175H in humans) are challenged by repeated induction of interferons. The protocol includes four weeks of serial injection with pIpC followed by a four-week recovery period, that repeats up to 3 times. Bone-marrow, spleen, thymic, and lymph node cells are stained for lymphoid and myeloid progeny, as well as for stem- and progenitors. FACS cytoflex is used for analysis. Despite clear changes during stimulation, we find little impact of the chronic long-term immune stimulation on most hematological parameters regardless of the status of p53 (wt and mutant p53 allele). However, mice with a mutant p53 allele treated with pIpC exhibited a large spleen, thymus, and lymph nodes. We observed the increased frequencies of CD8+ T cells but not CD4+ T cells in p53MUT mice, following chronic pIpC. In these experiments, p53MUT developed lymphoma while WT did not develop such malignancy during the same time. Our data suggest little direct damage to HSCs by the parameter tested so far, and a profound malignancy in the p53MUT mice following chronic stimulation. Hence, the cancerous impact of stress hematopoiesis might drive malignancy at different levels of the hematopoietic system.

Evaluation of alpaca tracheal explants as an ex vivo model for the study of Middle East respiratory syndrome coronavirus (MERS-CoV) infection

Middle East respiratory syndrome coronavirus (MERS-CoV) poses a serious threat to public health. Here, we established an ex vivo alpaca tracheal explant (ATE) model using an air-liquid interface culture system to gain insights into MERS-CoV infection in the camelid lower respiratory tract. ATE can be infected by MERS-CoV, being 103 TCID50/mL the minimum viral dosage required to establish a productive infection. IFNs and antiviral ISGs were not induced in ATE cultures in response to MERS-CoV infection, strongly suggesting that ISGs expression observed in vivo is rather a consequence of the IFN induction occurring in the nasal mucosa of camelids.

Abstract P047: Inactivation of IFN signaling drive immunosuppressive MDSC function and can be therapeutically targeted

Abstract Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity that promote tumor progression and impair the efficacy of anti-tumor therapeutics. Herein we show that type I interferons (IFN1) receptor dampen immune suppressive activity of MDSC. Downregulation of the IFNAR1 is found in MDSC from cancer patients and mouse tumor models. Downregulation of IFNAR1 depends on the activation of the p38 protein kinase and is required for activation of the immune suppressive phenotype moreover genetic stabilization of IFNAR1 in tumor bearing mice reduces suppressive activity of MDSC and promote antitumor effect. Stabilizing IFNAR1 using inhibitor of p38 combined with the interferon induction therapy elicits a robust anti-tumor effect that is completely dependent on IFNAR1 expression on MDSC. Thus, inhibition of MDSC immune suppressive function can be exploited therapeutically. Citation Format: Emilio Sanseviero, Kevin Alicea-Torres, Yulia Nefedova, Serge Y. Fuchs, Dmitry I. Gabrilovich. Inactivation of IFN signaling drive immunosuppressive MDSC function and can be therapeutically targeted [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P047.

Human STING Is Regulated by an Autoinhibitory Mechanism for Type I Interferon Production

Stimulator of interferon genes (STING) plays a pivotal role in type I interferon-mediated innate immune response to the cytoplasmic detection of aberrant DNA. STING is a membrane protein localized in endoplasmic reticulum (ER), which upon stimulation translocates to Golgi apparatus and activates downstream signaling cascades. However, the mechanism regulating STING activity and significance of its intracellular traffic are not completely understood. Here we identify a novel region of human STING comprising thirteen residues within its C-terminal tail (CTT) for downstream nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation. We also discover that STING CTT fragment can activate downstream signaling regardless of its ER localization. In addition, we reveal that ligand-binding domain (LBD) in the middle of STING binds and confers autoinhibition to its CTT for both NF-κB- and interferon regulatory factor 3-activation. Furthermore, STING LBD can inhibit the interferon-stimulating activity of STING CTT in trans and demonstrate a dominant negative effect on endogenous STING for interferon induction. We thus uncover an important autoinhibitory mechanism modulating STING activity.

ИНДУКТОРЫ ЭНДОГЕННОГО ИНТЕРФЕРОНА В РЯДУ 6-АРИЛАМИНО-ПИРИМИДИН-2,4(1H,3H)-ДИОНОВ: ОТ ДИЗАЙНА К ПРАКТИКЕ

A series of 6-arylaminopyrimidine-2,4(1H,3H)-diones were synthesized via transamination of 6-aminouracil. Among the target compounds, 3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-yl)aminobenzoic acid methyl ester proved to be an effective endogenous interferon inducer. During biological evaluation followed by a patenting procedure, the ester was assigned the ImmuVag international nonproprietary name.

PolyI:C attenuates transforming growth factor-β signaling to induce cytostasis of surrounding cells by secreted factors in triple-negative breast cancer.

The activation of RIG‐I‐like receptor (RLR) signaling in cancer cells is widely recognized as a critical cancer therapy method. The expected mechanism of RLR ligand‐mediated cancer therapy involves the promotion of cancer cell death and strong induction of interferon (IFN)‐β that affects the tumor microenvironment. We have recently shown that activation of RLR signaling in triple‐negative breast cancer cells (TNBC) attenuates transforming growth factor‐β (TGF‐β) signaling, which partly contributes to the promotion of cancer cell pyroptosis. However, the consequences of suppression of TGF‐β signaling by RLR ligands with respect to IFN‐β‐mediated tumor suppression are not well characterized. This study showed that transfection of a typical RLR ligand polyI:C in cancer cells produces significant levels of IFN‐β, which inhibits the growth of the surrounding cancer cells. In addition, IFN‐β‐induced cell cycle arrest in surrounding cancer cells was inhibited by the expression of constitutively active Smad3. Constitutively active Smad3 suppresses IFN‐β expression through the alleviation of IFN regulatory factor 3 binding to the canonical target genes, as suggested by ChIP sequencing analysis. Based on these findings, a new facet of the protumorigenic function of TGF‐β that suppresses IFN‐β expression is suggested when RLR‐mediated cancer treatment is used in TNBC.

STING-Mediated Interferon Induction by Herpes Simplex Virus 1 Requires the Protein Tyrosine Kinase Syk

ABSTRACTThe nature and the intensity of innate immune response to virus infection determine the course of pathogenesis in the host. Among the many pathogen-associated molecular pattern recognition receptors, STING, an endoplasmic reticulum (ER)-associated protein, plays a pivotal role in triggering responses to microbial or cellular cytoplasmic DNA. Herpes simplex virus 1 (HSV-1), a common human pathogen, activates STING signaling, and the resultant induction of type I interferon causes inhibition of virus replication. In this context, we have observed that phosphorylation of Tyr245 of STING by epidermal growth factor receptor kinase is necessary for interferon induction. Here, we report that phosphorylation of Tyr240 by the tyrosine kinase Syk is essential for all signaling activities of STING. Our analysis showed that upon ligand-binding, STING dimerizes and interacts with membrane-bound EGFR, which autophosphorylates and provides the platform for the recruitment of cytoplasmic Syk to the signaling complex and its activation. Activated Syk phosphorylates Tyr240 of STING, followed by phosphorylation of Tyr245 by epidermal growth factor receptor (EGFR). Pharmacological or genetic ablation of Syk activity resulted in an arrest of STING in the ER compartment and a complete block of gene induction. Consequently, in the absence of Syk, HSV-1 could not induce interferon, and it replicated more robustly.

TBK1 recruitment to STING mediates autoinflammatory arthritis caused by defective DNA clearance.

Defective DNA clearance in DNase II-/- mice leads to lethal inflammatory diseases that can be rescued by deleting cGAS or STING, but the role of distinct signaling pathways downstream of STING in the disease manifestation is not known. We found that the STING S365A mutation, which abrogates IRF3 binding and type I interferon induction, rescued the embryonic lethality of DNase II-/- mice. However, the STING S365A mutant retains the ability to recruit TBK1 and activate NF-κB, and DNase II-/-STING-S365A mice exhibited severe polyarthritis, which was alleviated by neutralizing antibodies against TNF-α or IL-6 receptor. In contrast, the STING L373A mutation or C-terminal tail truncation, which disrupts TBK1 binding and therefore prevents activation of both IRF3 and NF-κB, completely rescued the phenotypes of DNase II-/- mice. These results demonstrate that TBK1 recruitment to STING mediates autoinflammatory arthritis independently of type I interferons. Inhibiting TBK1 binding to STING may be a therapeutic strategy for certain autoinflammatory diseases instigated by self-DNA.

Mayaro Virus Non-Structural Protein 2 Circumvents the Induction of Interferon in Part by Depleting Host Transcription Initiation Factor IIE Subunit 2.

Mayaro virus (MAYV) is an emerging mosquito-transmitted virus that belongs to the genus Alphavirus within the family Togaviridae. Humans infected with MAYV often develop chronic and debilitating arthralgia and myalgia. The virus is primarily maintained via a sylvatic cycle, but it has the potential to adapt to urban settings, which could lead to large outbreaks. The interferon (IFN) system is a critical antiviral response that limits replication and pathogenesis of many different RNA viruses, including alphaviruses. Here, we investigated how MAYV infection affects the induction phase of the IFN response. Production of type I and III IFNs was efficiently suppressed during MAYV infection, and mapping revealed that expression of the viral non-structural protein 2 (nsP2) was sufficient for this process. Interactome analysis showed that nsP2 interacts with DNA-directed RNA polymerase II subunit A (Rpb1) and transcription initiation factor IIE subunit 2 (TFIIE2), which are host proteins required for RNA polymerase II-mediated transcription. Levels of these host proteins were reduced by nsP2 expression and during infection by MAYV and related alphaviruses, suggesting that nsP2-mediated inhibition of host cell transcription is an important aspect of how some alphaviruses block IFN induction. The findings from this study may prove useful in design of vaccines and antivirals, which are currently not available for protection against MAYV and infection by other alphaviruses.

Gill Transcriptomic Responses to Toxin-producing Alga Prymnesium parvum in Rainbow Trout.

The gill of teleost fish is a multifunctional organ involved in many physiological processes, including protection of the mucosal gill surface against pathogens and other environmental antigens by the gill-associated lymphoid tissue (GIALT). Climate change associated phenomena, such as increasing frequency and magnitude of harmful algal blooms (HABs) put extra strain on gill function, contributing to enhanced fish mortality and fish kills. However, the molecular basis of the HAB-induced gill injury remains largely unknown due to the lack of high-throughput transcriptomic studies performed on teleost fish in laboratory conditions. We used juvenile rainbow trout (Oncorhynchus mykiss) to investigate the transcriptomic responses of the gill tissue to two (high and low) sublethal densities of the toxin-producing alga Prymnesium parvum, in relation to non-exposed control fish. The exposure time to P. parvum (4–5 h) was sufficient to identify three different phenotypic responses among the exposed fish, enabling us to focus on the common gill transcriptomic responses to P. parvum that were independent of dose and phenotype. The inspection of common differentially expressed genes (DEGs), canonical pathways, upstream regulators and downstream effects pointed towards P. parvum-induced inflammatory response and gill inflammation driven by alterations of Acute Phase Response Signalling, IL-6 Signalling, IL-10 Signalling, Role of PKR in Interferon Induction and Antiviral Response, IL-8 Signalling and IL-17 Signalling pathways. While we could not determine if the inferred gill inflammation was progressing or resolving, our study clearly suggests that P. parvum blooms may contribute to the serious gill disorders in fish. By providing insights into the gill transcriptomic responses to toxin-producing P. parvum in teleost fish, our research opens new avenues for investigating how to monitor and mitigate toxicity of HABs before they become lethal.

Cross-species analysis of viral nucleic acid interacting proteins identifies TAOKs as innate immune regulators

The cell intrinsic antiviral response of multicellular organisms developed over millions of years and critically relies on the ability to sense and eliminate viral nucleic acids. Here we use an affinity proteomics approach in evolutionary distant species (human, mouse and fly) to identify proteins that are conserved in their ability to associate with diverse viral nucleic acids. This approach shows a core of orthologous proteins targeting viral genetic material and species-specific interactions. Functional characterization of the influence of 181 candidates on replication of 6 distinct viruses in human cells and flies identifies 128 nucleic acid binding proteins with an impact on virus growth. We identify the family of TAO kinases (TAOK1, −2 and −3) as dsRNA-interacting antiviral proteins and show their requirement for type-I interferon induction. Depletion of TAO kinases in mammals or flies leads to an impaired response to virus infection characterized by a reduced induction of interferon stimulated genes in mammals and impaired expression of srg1 and diedel in flies. Overall, our study shows a larger set of proteins able to mediate the interaction between viral genetic material and host factors than anticipated so far, attesting to the ancestral roots of innate immunity and to the lineage-specific pressures exerted by viruses.

Airway Epithelial Innate Immunity.

Besides providing an essential protective barrier, airway epithelial cells directly sense pathogens and respond defensively. This is a frontline component of the innate immune system with specificity for different pathogen classes. It occurs in the context of numerous interactions with leukocytes, but here we focus on intrinsic epithelial mechanisms. Type 1 immune responses are directed primarily at intracellular pathogens, particularly viruses. Prominent stimuli include microbial nucleic acids and interferons released from neighboring epithelial cells. Epithelial responses revolve around changes in the expression of interferon-sensitive genes (ISGs) that interfere with viral replication, as well as the further induction of interferons that signal in autocrine and paracrine manners. Type 2 immune responses are directed primarily at helminths and fungi. Prominent pathogen stimuli include proteases and chitin, and important responses include mucin hypersecretion and chitinase release. Type 3 immune responses are directed primarily at extracellular microbial pathogens, including bacteria and fungi, as well as viruses during their extracellular phase of infection. Prominent microbial stimuli include bacterial wall components, such as lipopeptides and endotoxin, as well as microbial nucleic acids. Key responses are the release of reactive oxygen species (ROS) and antimicrobial peptides (AMPs). For all three types of response, paracrine signaling to neighboring epithelial cells induces resistance to infection over a wide field. Often, the epithelial effector molecules themselves also have signaling properties, in addition to the release of inflammatory cytokines that boost local innate immunity. Together, these epithelial mechanisms provide a powerful first line of pathogen defense, recruit leukocytes, and instruct adaptive immune responses.

Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses - are we our own worst enemy?

Human coronaviruses cause a wide spectrum of disease, ranging from mild common colds to acute respiratory distress syndrome and death. Three highly pathogenic human coronaviruses — severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus and SARS-CoV-2 — have illustrated the epidemic and pandemic potential of human coronaviruses, and a better understanding of their disease-causing mechanisms is urgently needed for the rational design of therapeutics. Analyses of patients have revealed marked dysregulation of the immune system in severe cases of human coronavirus infection, and there is ample evidence that aberrant immune responses to human coronaviruses are typified by impaired induction of interferons, exuberant inflammatory responses and delayed adaptive immune responses. In addition, various viral proteins have been shown to impair interferon induction and signalling and to induce inflammasome activation. This suggests that severe disease associated with human coronaviruses is mediated by both dysregulated host immune responses and active viral interference. Here we discuss our current understanding of the mechanisms involved in each of these scenarios.

Influenza virus vector iNS1 expressing bovine papillomavirus 1 (BPV1) antigens efficiently induces tumour regression in equine sarcoid patients.

Bovine papillomaviruses types 1 and 2 (BPV1, BPV2) commonly induce skin tumours termed sarcoids in horses and other equids. Sarcoids seriously compromise the health and welfare of affected individuals due to their propensity to resist treatment and reoccur in a more severe form. We have developed influenza (Flu) A and B virus vectors that harbour a truncated NS1 gene (iNS) assuring interferon induction and co-express shuffled BPV1 E6 and E7 antigens for sarcoid immunotherapy. In a safety trial involving 12 healthy horses, intradermal administration of iNSA/E6E7equ and iNSB/E6E7equ was well tolerated, with the only transient side effect being mild fever in four horses. Repeated screening of secretions and faeces by RT-PCR and plaque assay revealed no virus shedding, thus also confirming biological safety. In a patient trial involving 29 horses bearing BPV1-induced single or multiple sarcoids, at least one lesion per horse was intratumourally injected and then boosted with iNSA/E6E7equ and/or iNSB/E6E7equ. The treatment induced a systemic antitumour response as reflected by the synchronous regression of injected and non-injected lesions. Irrespective of vaccination schemes, complete tumour regression was achieved in 10/29 horses. In 10/29 horses, regression is still ongoing (May 2021). Intriguingly, scrapings collected from former tumour sites in two patients tested negative by BPV1 PCR. Nine severely affected individuals with a history of unsuccessful therapeutic attempts did not (6/29) or only transiently (3/29) respond to the treatment. INSA/E6E7equ and iNSB/E6E7equ proved safe and effective in significantly reducing the tumour burden even in severe cases.

Current opportunities and prospectives of immunotropic therapy in chronic generalized periodontitis

Impairment of immunological reactivity in inflammatory periodontal diseases is well proven. To perform immunomodulatory treatment in domestic dental practice, various medications are used, including natural, chemically modified, recombinant, genetically engineered and synthetic substances, which differ in their effects upon innate and adaptive immune systems. Complex preparations of natural cytokines as well as genetically engineered preparations of IL-1, IL-2, growth factors, IFNα, IFNβ, IFNγ are applied in clinical settings. Clinical implementation of interferon and interferon inducers in combined therapy of generalized periodontitis is shown to increase resistance to viral components of the oral microbiota. Growth factors (platelet growth factor, fibroblast growth factor, endothelial growth factor, etc.) are successfully used for tissue regeneration in periodontics and maxillofacial surgery. Experimental studies have shown that local administration of toll-like receptor-9 and CD40 ligand may reduce periodontal ligature inflammation and bone loss in mice by inducing B-cell proliferation and increasing IL-10 mRNA expression. Promising results in development of new biologically active drugs are obtained with nanotechnology approaches, i.e., production of composite materials of metal nanoparticles with polymers, growth factors, and local application of these products. General limitations of all these growth factors include extremely short periods of biological activity, and adjusted duration of local effective concentrations. Therefore, it is important to develop a drug delivery system using appropriate scaffolding elements thus allowing local effects of the drug for a certain period of time. In experimental models, alginate hydrogels performed well upon local delivery of granulocyte-macrophage colony-stimulating factor and stromal lymphopoietin of the thymus. A new immunomodulatory strategy for alveolar bone regeneration targets macrophages. A biologically functionalized injectable microsphere of heparin-modified gelatin nanofibers that mimic the architecture of the natural bone extracellular matrix, and provide an osteoconductive microenvironment for bone cells includes IL-4, which has heparin-binding domains. These medications represent a component of a comprehensive treatment schedule, and should be evaluated for immune status before and after therapy. Thus, recent advances in studies of innate and acquired immune responses in inflammatory diseases and, in particular, in periodontal disorders, allows us to develop new approaches and methods of treatment in order to improve efficiency of complex therapy in the inflammatory periodontal diseases.

Baculovirus Vectors Induce the Production of Interferons in Swine: Their Potential in the Development of Antiviral Strategies.

The huge variety of viruses affecting swine represents a global threat. Since vaccines against highly contagious viruses last several days to induce protective immune responses, antiviral strategies for rapid control of outbreak situations are needed. The baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV), an insect virus, has been demonstrated to be an effective vaccine vector for mammals. Besides the ability to display or transduce heterologous antigens, it also induces strong innate immune responses and provides IFN-mediated protection against lethal challenges with viruses like foot-and-mouth disease virus (FMDV) in mice. Thus, the aim of this study was to evaluate the ability of AcMNPV to induce IFN production and elicit antiviral activity in porcine peripheral blood mononuclear cells (PBMCs). Our results demonstrated that AcMNPV induced an IFN-α-mediated antiviral activity in PBMCs in vitro. Moreover, the inoculation of AcMNPV in piglets led to the production of type I and II IFNs in sera from inoculated animals and antiviral activities against vesicular stomatitis virus (VSV) and FMDV measured by in vitro assays. Finally, it was demonstrated that the pseudotyping of AcMNPV with VSV-G protein, but not the enrichment of the AcMNPV genome with specific immunostimulatory CpG motifs for the porcine TLR9, improved the ability to induce IFN-α production in PBMCs in vitro. Together, these results suggest that AcMNPV is a promising tool for the induction of IFNs in antiviral strategies, with the potential to be biotechnologically improved.

Molecular and clinical effects of selective tyrosine kinase 2 inhibition with deucravacitinib in psoriasis

Psoriasis, a chronic inflammatory disease dependent on the IL-23/TH17 pathway, is initiated through plasmacytoid dendritic cell activation and type I IFN induction in the skin. Deucravacitinib, a selective tyrosine kinase 2 (TYK2) inhibitor, blocks IL-23, IL-12, and type I IFN signaling in cellular assays. We investigated changes in IL-23/TH17 and type I IFN pathway biomarkers and gene responses as well as measures of selectivity for TYK2 over Janus kinases (JAKs) 1-3 in patients with moderate to severe psoriasis receiving deucravacitinib. Deucravacitinib was evaluated in a randomized, placebo-controlled, dose-ranging trial. Biopsy samples from nonlesional (day 1) and lesional skin (days 1, 15, and 85) were assessed for changes in IL-23/IL-12 and type I IFN pathway biomarkers by quantitative reverse-transcription polymerase chain reaction, RNA sequencing, and immunohistochemistry. Laboratory markers were measured in blood. Percentage change from baseline in Psoriasis Area and Severity Index (PASI) score was assessed. IL-23 pathway biomarkers in lesional skin returned toward nonlesional levels dose-dependently with deucravacitinib. IFN and IL-12 pathway genes were normalized. Markers of keratinocyte dysregulation, keratin-16, and β-defensin genes approached nonlesional levels with effective doses. Select laboratory parameters affected by JAK1-3 inhibition were not affected by deucravacitinib. Greater improvements in PASI scores, correlated with biomarker changes, were seen with the highest doses of deucravacitinib versus lower doses or placebo. Robust clinical efficacy with deucravacitinib treatment was associated with decreases in IL-23/TH17 and IFN pathway biomarkers. The lack of effect seen on biomarkers specific to JAK1-3 inhibition supports selectivity of deucravacitinib for TYK2; larger confirmatory studies are needed.

Erythrocyte-derived mitochondria: an unexpected interferon inducer in lupus

Type 1 interferon (IFN) is a major contributor to the pathogenesis of systemic lupus erythematosus (SLE). A landmark study by Caielli et al. now shows that erythrocytes from lupus patients that fail to switch from glycolysis to oxidative phosphorylation during differentiation retain their mitochondria. These mitochondria-containing erythrocytes represent a novel source of IFN when phagocytosed by macrophages.

Changes in MDA5 and TLR3 Sensing of the Same Diabetogenic Virus Result in Different Autoimmune Disease Outcomes.

Seemingly redundant in function, melanoma differentiation-associated protein 5 (MDA5) and toll-like receptor- 3 (TLR3) both sense RNA viruses and induce type I interferon (IFN-I). Herein, we demonstrate that changes in sensing of the same virus by MDA5 and TLR3 can lead to distinct signatures of IFN-α and IFN-ß resulting in different disease outcomes. Specifically, infection with a diabetogenic islet β cell-tropic strain of coxsackievirus (CB4) results in diabetes protection under reduced MDA5 signaling conditions while reduced TLR3 function retains diabetes susceptibility. Regulating the induction of IFN-I at the site of virus infection creates a local site of interferonopathy leading to loss of T cell regulation and induction of autoimmune diabetes. We have not demonstrated another way to prevent T1D in the NOD mouse, rather we believe this work has provided compounding evidence for a specific control of IFN-I to drive a myriad of responses ranging from virus clearance to onset of autoimmune diabetes.