Interféron | EPFL Graph Search

Les interférons (IFN) sont des protéines (glycoprotéines de la famille des cytokines). Ils sont naturellement produits par les cellules du système immunitaire, mais également par d'autres types cellulaires (cellules dendritiques, mononucléées, épithéliales) en fonction des sous types. Chez la plupart des vertébrés, ils sont produits en réponse à la présence d'une double hélice d'ARN étranger dans l'organisme (plus généralement par la présence de structures moléculaires associées à des pathogènes). Ils ont pour effet de défendre l'organisme des agents pathogènes tels les virus, bactéries, parasites et cellules tumorales. Ils le font en induisant la production de protéines de la fonction immunitaire (notamment antivirales et anti-bactériennes, ou à effet sur la réponse immune, et à visée anti-prolifératives). Leur nom d'interféron donné en 1957 par Isaacs et Lindenman vient du fait qu'ils interfèrent avec la réplication virale dans les cellules de l'hôte, en activant des cellules NK

Identification and characterisation of small-molecule inhibitors targeting STING

Simone Margret Haag

The recognition of pathogen-derived nucleic acids is a critical mechanism by which the innate immune system detects viral infection. Upon activation, nucleic acid sensors initiate the expression of type I interferons and other inflammatory mediators, subsequently leading to potent antiviral immune responses. However, erroneous detection of nucleic acids can have deleterious consequences for the host by inducing the development of certain autoinflammatory disorders. Inappropriate sensing of self- nucleic acids underlies a spectrum of monogenic disease referred to as type interferonopathies, including the Aicardi-Goutières syndrome (AGS). These disorders are often driven by mutations in genes encoding for components of nucleic acid recognition pathways, thereby resulting in the constitutive activation of type I interferon responses. Insight into the molecular pathology of AGS has highlighted promising new targets that may be harnessed for the development of novel therapeutics to counter this disorder. Stimulator of interferon genes (STING) - a central adaptor of the cytosolic DNA sensing pathway - has been strongly implicated in the pathogenesis of distinct inflammatory disorders, including AGS. Therefore, pharmacological inhibition of STING presents a promising approach for the development of potent treatment strategies against these and potentially other STING-mediated, autoinflammatory diseases. Performing a cell-based small-molecule screen, we identified and characterized two series of compounds, which potently and selectively inhibit STING through a mechanism that blocks the activation-induced palmitoylation of STING. The identified small-molecules mediate this inhibition through covalent binding to a transmembrane predicted cysteine residue (Cys91) - a palmitoylation site required for STING activation. Using the inhibitors, we show that the palmitoylation of STING mediates the formation of multimeric complexes at the Golgi and the subsequent recruitment and activation of the direct downstream kinase TBK1. We also provide evidence that representatives of both identified compound classes potently inhibit STING-induced expression of inflammatory cytokines including type I interferon, in human and mouse cells. Furthermore, we also demonstrate that the identified STING inhibitors attenuate autoinflammatory disease features in a mouse model of AGS. Taken together, this work uncovers a small-molecule mediated mechanism to inhibit STING and demonstrates the pharmacological potential of targeting STING for the treatment of type I interferon driven disease such as AGS.

EPFL2019

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Jie Chen, Xavier Duval, Jacques Fellay, Ji Hoon Han, Juan Li, Zhiyong Liu, Rui Yang, Peng Zhang, Qian Zhang, Yu Zhang

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3-and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

AMER ASSOC ADVANCEMENT SCIENCE2020

Polynucleotide cytidine deaminases, innate immunity and hepatitis B infection

Stéphanie Jost

More than 350 millions individuals worldwide suffer from chronic hepatitis B virus (HBV) infection, a condition that evolves towards liver insufficiency and hepatocellular carcinoma in approximately 15 to 40 percent of cases. Yet the majority of de novo HBV infections, except for those occurring during the perinatal period, are cleared during the acute phase. This largely appears to result from non-cytopathic host defense mechanisms involving cytokines and notably interferons (IFNs). A key role for IFNs in the biology of HBV infection has been further illustrated by studies in animal models of the disease. Besides, IFN-α is the standard treatment for chronic hepatitis B. Although type I and II IFNs are the most important immune-regulators of HBV replication, the downstream effectors mediating the inhibitory action of IFNs on HBV replication have not yet been identified. In a first place we showed that HBV replication is blocked by human APOBEC3G and APOBEC3F, two closely related editing enzymes belonging to the family of polynucleotide cytidine deaminases, whose catalytic activity results in the conversion of cytidine residues to uridine residues. Both proteins were initially recognized for their ability to inhibit retroviruses, a property which mainly depends on their editing activity, and as the targets of the virion infectivity factor (Vif) protein of human immunodeficiency virus (HIV), which induces their degradation. The family of polynucleotide cytidine deaminases also comprises Activation-Induced cytidine Deaminase (AID), APOBEC1, APOBEC2, and the products of the APOBEC3A through APOBEC3H gene cluster. AID is essential for class switch recombination and somatic hypermutation of the immunoglobulin locus in pre-B lymphocytes, thus for the generation of antibody diversity, and APOBEC1 edits the apolipoprotein B mRNA in the guts, thereby regulating cholesterol metabolism. By comparison, little is known about the physiological functions of the other family members. However, apart from APOBEC2 and APOBEC3A, sequence analysis of the genes encoding these enzymes suggested that they possibly evolved as a host defense against pathogens. This hypothesis was confirmed for most of APOBEC3 proteins, which were independently found to restrict the replication of various exogenous and endogenous retroelements, as well as the adeno-associated virus. For this reason, we next explored the range of cytidine deaminases active on HBV and found that besides APOBEC3G and APOBEC3F, APOBEC3B, AID and APOBEC1 are also potent inhibitors of HBV. In parallel, while examining in details the mechanisms underlying the antiviral activity of APOBEC3G against HBV, we found that this cytidine deaminase blocks HBV infection not by lethal editing of nascent reverse transcripts, as for retroviruses, but rather by impairing the accumulation of pregenomic RNA (pgRNA)-containing viral capsids, the subviral structures in which HBV reverse transcription takes place before virions containing a partially double-stranded DNA genome are released. Remarkably, this is similar to the decreased steady-state levels of pgRNA-containing capsids which are observed upon exposure of HBV infected cells to IFNs. It suggested that IFNs and cytidine deaminases might affect HBV replication through the same pathway. The first step to unveil the in vivo relevance of antiviral cytidine deaminases for the control of HBV replication consisted in our demonstration that type I and II IFN treatment of human hepatocytes induces the production of APOBEC3G, and to a smaller extent, that of APOBEC3F and APOBEC3B, but not that of AID and APOBEC1. These observations led us to ask whether the induction of antiviral cytidine deaminases by cytokines contributes to the IFN-induced clearance of HBV, as IFN-α and IFN-γ are both found in high amounts in the liver of acutely infected individuals. Importantly, we revealed that blocking APOBEC3G, APOBEC3F and APOBEC3B in hepatic cell lines does not abrogate the inhibitory effect of IFNs on HBV, indicating that antiviral cytidine deaminases are not the main mediators of the action of IFNs on this pathogen. Nevertheless, while HBV replication was not impaired in hepatic cells when these enzymes were expressed at their baseline levels, they could edit the HBV genome in these conditions, suggesting that cytidine deaminases might participate in the emergence of new HBV strains, notably those that have been recognized as being of clinical importance. Finally, the results of this work indicate that a therapeutic strategy based on the expression of antiviral cytidine deaminases in the liver could be envisioned to cure HBV chronic infections.

EPFL2007