Induction of type I interferons by bacteria

Type I interferons (IFNs) are secreted cytokines that orchestrate diverse immune responses to infection. Although typically considered to be most important in the response to viruses, type I IFNs are also induced by most, if not all, bacterial pathogens. Although diverse mechanisms have been described, bacterial induction of type I IFNs occurs upon stimulation of two main pathways: (i) Toll‐like receptor (TLR) recognition of bacterial molecules such as lipopolysaccharide (LPS); (ii) TLR‐independent recognition of molecules delivered to the host cell cytosol. Cytosolic responses can be activated by two general mechanisms. First, viable bacteria can secrete stimulatory ligands into the cytosol via specialized bacterial secretion systems. Second, ligands can be released from bacteria that lyse or are degraded. The bacterial ligands that induce the cytosolic pathways remain uncertain in many cases, but appear to include various nucleic acids. In this review, we discuss recent advances in our understanding of how bacteria induce type I interferons and the roles type I IFNs play in host immunity.     

Genetic associations in type I interferon related pathways with autoimmunity

Type I interferons play an outstanding role in innate and adaptive immunity by enhancing functions of dendritic cells, inducing differentiation of monocytes, promoting immunoglobulin class switching in B cells and stimulating effector functions of T cells. The increased production of IFNα/β by plasmacytoid dendritic cells could be responsible for not only efficient antiviral defence, but it also may be a pathological factor in the development of various autoimmune disorders. The first evidence of a genetic link between type I interferons and autoimmune diseases was the observation that elevated IFNα activity is frequently detected in the sera of patients with systemic lupus erythematosus, and that this trait shows high heritability and familial aggregation in their first-degree healthy relatives. To date, a number of genes involved in interferon signalling have been associated with various autoimmune diseases. Patients with systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, psoriasis, and a fraction of patients with rheumatoid arthritis display a specific expression pattern of interferon-dependent genes in their leukocytes, termed the interferon signature. Here, in an attempt to understand the role of type I interferons in the pathogenesis of autoimmunity, we review the recent advances in the genetics of autoimmune diseases focusing on the association of genes involved in type I interferon pathways.     

The influence of type I interferons on immune cells can be mediated through regulation of estrogen receptor alpha level

Autoimmune disorders are connected with the actions of sex hormones. Clinical observations have shown that especially estrogens are involved in these phenomena. In some cases the administration of estrogens can increase the pathological symptoms of a disorder, while in others they can cause disease remission. In multiple autoimmune diseases, type I interferons, a family of cytokines acting through the common receptor IFNAR1/IFNAR2, seem to have action convergent with that of estrogens. We hypothesize that this coincidence is not accidental and type I interferons can regulate the level of estrogen receptor alpha (ERα) and consequently change the sensitivity of immune cells to estrogen's action. There is evidence that ERα is responsible for the effects exerted by estrogens and that this phenomenon mainly involves antigen-presenting cells. On the other hand, research on IFN-tau, a type I interferon family members, showed that this cytokine can modulate ERα levels in ovine endometrium. Because of the common receptor for these interferons, we suspect that other type I interferons can act in this way not only in endometrial cells, but also in immune cells. If there is such a mechanism, it can be exploited in the therapy of immune disorders, especially autoimmune disease, for example through simultaneous administration of less toxic interferons and estrogens.     

甲型流感病毒感染过程中干扰素介导的天然免疫应答机制

甲型流感病毒作为引起人类和动物急性呼吸道传染病的一个主要病原体,在世界范围内广泛流行。研究表明,甲型流感病毒感染宿主后会诱导宿主的天然免疫应答。甲型流感病毒感染可引起Toll样受体(Toll like receptors,TLRs)和RIG-Ⅰ样受体(RIG-Ⅰ like receptors,RLRs)等宿主模式识别受体介导的抗病毒信号通路的活化,并在多种机制调控下诱导干扰素和其他细胞因子的表达,如Ⅰ型干扰素、Ⅲ型干扰素等,从而启动干扰素刺激基因(Interferon stimulated genes,ISGs)的转录及其抗病毒蛋白的表达,进而实现抗病毒作用。本文就甲型流感病毒感染与干扰素介导的天然免疫应答相关的信号通路和调控机制进行综述。     

Essential Role for the Mnk Pathway in the Inhibitory Effects of Type I Interferons on Myeloproliferative Neoplasm (MPN) Precursors

The mechanisms of generation of the antineoplastic effects of interferons (IFNs) in malignant hematopoietic cells remain to be precisely defined. We examined the activation of type I IFN-dependent signaling pathways in malignant cells transformed by Jak2V617F, a critical pathogenic mutation in myeloproliferative neoplasms (MPNs). Our studies demonstrate that during engagement of the type I IFN receptor (IFNAR), there is activation of Jak-Stat pathways and also engagement of Mnk kinases. Activation of Mnk kinases is regulated by the Mek/Erk pathway and is required for the generation of IFN-induced growth inhibitory responses, but Mnk kinase activation does not modulate IFN-regulated Jak-Stat signals. We demonstrate that for type I IFNs to exert suppressive effects in malignant hematopoietic progenitors from patients with polycythemia vera, induction of Mnk kinase activity is required, as evidenced by studies involving pharmacological inhibition of Mnk or siRNA-mediated Mnk knockdown. Altogether, these findings provide evidence for key and essential roles of the Mnk kinase pathway in the generation of the antineoplastic effects of type I IFNs in Jak2V617F-dependent MPNs.     

Modeling an immune response to influenza A virus infection in alveolar epithelial cells

Influenza A viruses (IAV) have been the cause of several influenza pandemics in history and are a significant threat for the next global pandemic. Hospitalized influenza patients often have excess interferon production and a dysregulated immune response to the IAV infection. Obtaining a better understanding of the mechanisms of IAV infection that induce these harmful effects would help drug developers and health professionals create more effective treatments for IAV infection and improve patient outcomes. IAV stimulates viral sensors and receptors expressed by alveolar epithelial cells, like RIG-I and toll-like receptor 3 (TLR3). These two pathways coordinate with one another to induce expression of type III interferons to combat the infection. Presented here is a queuing theory-based model of these pathways that was designed to analyze the timing and amount of interferons produced in response to IAV single stranded RNA and double-stranded RNA detection. The model accurately represents biological data showing the necessary coordination of the RIG-I and TLR3 pathways for effective interferon production. This model can serve as the framework for future studies of IAV infection and identify new targets for potential treatments.     

Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK

Induction of type I interferons can be triggered by viral components through Toll-like receptors or intracellular viral receptors such as retinoic acid-inducible gene I. Here, we demonstrate that the TRAF (tumor necrosis factor receptor-associated factor) family member-associated NF-kappaB activator (TANK) plays an important role in interferon induction through both retinoic acid-inducible gene I- and Toll-like receptor-dependent pathways. TANK forms complexes with both upstream signal mediators, such as Cardif/MAVS/IPS-1/VISA, TRIF (Toll-interleukin-1 receptor domain-containing adaptor inducing interferon-beta), and TRAF3 and downstream mediators TANK-binding kinase 1, inducible IkappaB kinase, and interferon regulatory factor 3. In addition, it synergizes with these signaling components in interferon induction. Specific knockdown of TANK results in reduced type I interferon production, increased viral titers, and enhanced cell sensitivity to viral infection. Thus, TANK may be a critical adaptor that regulates the assembly of the TANK-binding kinase 1-inducible IkappaB kinase complex with upstream signaling molecules in multiple antiviral pathways.     

Human immunodeficiency virus viremia induces plasmacytoid dendritic cell activation in vivo and diminished alpha interferon production in vitro

Human immunodeficiency virus type 1 (HIV-1) infection has been associated with perturbations of plasmacytoid dendritic cells (PDC), including diminished frequencies in the peripheral blood and reduced production of type I interferons (IFNs) in response to in vitro stimulation. However, recent data suggest a paradoxical increase in production of type 1 interferons in vivo in HIV-infected patients compared to uninfected controls. Using a flow cytometric assay to detect IFN-alpha-producing cells within unseparated peripheral blood mononuclear cells, we observed that short-term interruptions of antiretroviral therapy are sufficient to result in significantly reduced IFN-alpha production by PDC in vitro in response to CpG A ligands or inactivated HIV particles. The primary cause of diminished IFN-alpha production was reduced responsiveness of PDC to de novo stimulation, not diminished per cell IFN-alpha production or migration of cells to lymphoid organs. Real-time PCR analysis of purified PDC from patients prior to and during treatment interruptions revealed that active HIV-1 replication is associated with upregulation of type I IFN-stimulated gene expression. Treatment of hepatitis C virus-infected patients with IFN-alpha2b and ribavirin for hepatitis C virus infection resulted in a profound suppression of de novo IFN-alpha production in response to CpG A or inactivated HIV particles, similar to the response observed in HIV-infected patients. Together, these results suggest that diminished production of type I interferons in vitro by PDC from HIV-1-infected patients may not represent diminished interferon production in vivo. Rather, diminished function in vitro is likely a consequence of prior activation via type I interferons or HIV virions in vivo.     

Dissection of the interferon gamma-MHC class II signal transduction pathway reveals that type I and type II interferon systems share common signalling component(s).

We have used a herpes virus thymidine kinase (HSV-TK) based metabolic selection system to isolate mutants defective in the interferon gamma mediated induction of the MHC class II promoter. All the mutations act in trans and result in no detectable induction of MHC and invariant chain (Ii) gene expression. Scatchard analysis indicates that the mutants have a normal number of surface IFN gamma receptors with the same affinity constant. The mutants fall into two broad categories. One class of mutants is still able to induce MHC class I, IRF-1, 9-27, 1-8 and GBP genes by IFN gamma. A second class of mutants is defective for the IFN gamma induction of all the genes tested; surprisingly, the IFN alpha/beta induction of MHC class I, 9-27, ISG54 and ISG15 genes is also defective in these mutants, although different members of this class can be discriminated by the response of the GBP and IRF-1 genes to type I interferons. These data demonstrate that the signalling pathways of both type I and type II interferon systems share common signal transduction component(s). These mutants will be useful for the study of IFN gamma regulation of class II genes and Ii chain, and to elucidate molecular components of type I and type II interferon signal transduction.     

The host type I interferon response to viral and bacterial infections

Type I interferons (IFN) are well studied cytokines with anti-viral and immune-modulating functions. Type I IFNs are produced following viral infections, but until recently, the mechanisms of viral recognition leading to IFN production were largely unknown. Toll like receptors (TLRs) have emerged as key transducers of type I IFN during viral infections by recognizing various viral components. Furthermore, much progress has been made in defining the signaling pathways downstream of TLRs for type I IFN production. TLR7 and TLR9 have become apparent as universally important in inducing type I IFN during infection with most viruses, particularly by plasmacytoid dendritic cells. New intracellular viral pattern recognition receptors leading to type I IFN production have been identified. Many bacteria can also induce the up-regulation of these cytokines. Interestingly, recent studies have found a detrimental effect on host cells if type Ⅰ IFN is produced during infection with the intracellular gram-positive bacterial pathogen, Listeria monocytogenes. This review will discuss the recent advances made in defining the signaling pathways leading to type I IFN production.     

Type I interferon promotes cell‐to‐cell spread of Listeria monocytogenes

Type I interferons (IFNs) play a critical role in antiviral immune responses, but can be deleterious to the host during some bacterial infections. Listeria monocytogenes (Lm) induces a type I IFN response by activating cytosolic antiviral surveillance pathways. This is beneficial to the bacteria as mice lacking the type I IFN receptor (IFNAR1^?/?) are resistant to systemic infection by Lm. The mechanisms by which type I IFNs promote Lm infection are unclear. Here, we show that IFNAR1 is required for dissemination of Lm within infection foci in livers of infected mice and for efficient cell‐to‐cell spread in vitro in macrophages. IFNAR1 promotes ActA polarization and actin‐based motility in the cytosol of host cells. Our studies suggest type I IFNs directly impact the intracellular life cycle of Lm and provide new insight into the mechanisms used by bacterial pathogens to exploit the type I IFN response.     

Murine Toll-Like Receptor 2 Activation Induces Type I Interferon Responses from Endolysosomal Compartments

Background

Toll-like receptors (TLRs) are among the first-line sentinels for immune detection and responsiveness to pathogens. The TLR2 subfamily of TLRs (TLR1, TLR2, TLR6) form heterodimers with each other and are thus able to recognize a broad range of components from several microbes such as yeast, Gram-positive bacteria and protozoa. Until now, TLR2 activation by bacterial ligands has long been associated with pro-inflammatory cytokines but not type I interferon responses.

Methodology/Principal Findings

Using a variety of transgenic mice, here we provide in vivo and in vitro data showing that TLR2 activation does in fact induce interferon-beta and that this occurs via MyD88-IRF1 and -IRF7 pathways. Interestingly, by microscopy we demonstrate that although a cell surface receptor, TLR2 dependent induction of type I interferons occurs in endolysosomal compartments where it is translocated to upon ligand engagement. Furthermore, we could show that blocking receptor internalization or endolysosomal acidification inhibits the ability of TLR2 to trigger the induction type I interferon but not pro-inflammatory responses.

Conclusion/Significance

The results indicate that TLR2 activation induces pro-inflammatory and type I interferon responses from distinct subcellular sites: the plasma membrane and endolysosomal compartments respectively. Apart from identifying and characterizing a novel pathway for induction of type I interferons, the present study offers new insights into how TLR signaling discriminates and regulates the nature of responses to be elicited against extracellular and endocytosed microbes. These findings may also have clinical implication. Excessive production of pro-inflammatory cytokines and type I IFNs following activation of TLRs is a central pathologic event in several hyper-inflammatory conditions. The discovery that the induction of pro-inflammatory and type I IFN responses can be uncoupled through pharmacological manipulation of endolysosomal acidification suggests new avenues for potential therapeutic intervention against inflammations and sepsis.     

Transformation of mouse fibroblasts alters the induction pattern of type I IFNs after virus infection

Type I interferons (IFNs) have been shown to be involved in many immune defence and inflammatory responses. We here show that IFN-beta plays an absolute essential role in the efficient induction of all type I IFNs after infection of primary embryonic as well as primary adult fibroblasts with Sendai virus. In contrast, after immortalization of such fibroblasts with SV40 large T antigen, IFN-alpha4 can be induced independently of IFN-beta. However, efficient secretion of type I IFNs even in immortalized fibroblasts is only found when the complete signalling loop is induced by IFN-beta.     

Serum deprivation induced apoptosis in macrophage is mediated by autocrine secretion of type I IFNs

Apoptosis can be triggered by different forms of cellular stress. We here show that serum deprivation induces the expression and secretion of type I interferons and results in apoptosis in RAW 264.7 cell in a caspase dependent manner. Administration of either IFN-α or IFN-β antibody partially inhibits apoptosis while the two antibodies used together totally prevents RAW264.7 cell from apoptosis. GM-CSF, but not M-CSF and IL-3, protects serum deprivation induced apoptosis. Inhibition of JAKs also prevents macrophages from apoptosis. Activation of MAPKs is not required for serum deprivation induced apoptosis. Our results are the first to demonstrate that serum deprivation-induced apoptosis acts through autocrine secretion of type I interferons.     

Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab,an anti-IFNα antibody,in systemic lupus erythematosus

Type I interferons are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Type I interferon-inducible mRNAs are widely and concordantly overexpressed in the periphery and involved tissues of a subset of SLE patients, and provide utility as pharmacodynamic biomarkers to aid dose selection, as well as potential indicators of patients who might respond favorably to anti-IFNα therapy in SLE. We implemented a three-tiered approach to identify a panel of type I interferon-inducible mRNAs to be used as potential pharmacodynamic biomarkers to aid dose selection in clinical trials of sifalimumab, an anti-IFNα monoclonal antibody under development for the treatment of SLE. In a single-dose escalation phase 1 trial, we observed a sifalimumab-specific and dose-dependent inhibition of the overexpression of type I interferon-inducible mRNAs in the blood of treated subjects. Inhibition of expression of type I interferon-inducible mRNAs and proteins was also observed in skin lesions of SLE subjects from the same trial. Inhibiting IFNα resulted in a profound downstream effect in these SLE subjects that included suppression of mRNAs of B-cell activating factor belonging to the TNF family and the signaling pathways of TNFα, IL-10, IL-1β, and granulocyte-macrophage colony-stimulating factor in both the periphery and skin lesions. A scoring method based on the expression of type I interferon-inducible mRNAs partitioned SLE patients into two distinct subpopulations, which suggests the possibility of using these type I interferon-inducible genes as predictive biomarkers to identify SLE patients who might respond more favorably to anti-type I interferon therapy.