Roles of Type I and III Interferons in COVID-19.
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ABSTRACT:
SUBMITTER: Choi H
PROVIDER: S-EPMC8084697 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Coronavirus disease 2019 (COVID-19) is globally rampant, and to curb the growing burden of this disease, in-depth knowledge about its pathophysiology is needed. This was an observational study conducted at a single center to investigate serum cytokine and chemokine levels of COVID-19 patients, based on disease severity. We included 72 consecutive COVID-19 patients admitted to our hospital from March 21 to August 31, 2020. Patients were divided into Mild-Moderate I (mild) and Moderate II-Severe (severe) groups based on the COVID-19 severity classification developed by the Ministry of Health, Labor and Welfare (MHLW) of Japan. We compared the patient characteristics as well as the serum cytokine and chemokine levels on the day of admission between the two groups. Our findings indicated that the severe group had significantly higher levels of serum fibrinogen, d-dimer, lactate dehydrogenase, C-reactive protein, ferritin, Krebs von den Lungen-6, surfactant protein (SP)-D, and SP-A than the mild group. Strikingly, the levels of interleukin (IL)-28A/interferon (IFN)-λ2 were significantly lower in the severe group than in the mild group. We believe that reduced levels of type III interferons (IFN-λs) and alterations in the levels of other cytokines and chemokines may impact the severity of the disease.
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Project description:The COVID-19 pandemic has caused millions of deaths and has resulted in disastrous societal and economic impacts worldwide. During SARS-CoV-2 infection, abnormal levels of pro-inflammatory cytokines have been observed and were associated to the severity of the disease. Type I (-α/β) and Type III (IFN-λ) interferons are family members of cytokines that play an important role in fighting viral replication during the early phases of infection. The location and timing of the IFNs production have been shown to be decisive for the COVID-19 outcome. Despite the effectiveness of COVID-19 vaccines and with the emergence of new SARS-CoV-2 variants, a better understanding of the involvement of IFNs as players in antiviral immunity in the COVID-19 pathophysiology is necessary to implement additional potent prophylactic and/or therapeutic approaches. In this study, we investigated the role of type I and III IFN in COVID-19 pathophysiology. We first analyzed the IFN-α, IFN-β and IFN- λ mRNA expression in nasopharyngeal swabs and blood samples from Moroccan patients infected with SARS-CoV-2 and secondly correlated these IFNs expressions with COVID-19 clinical and biological parameters. Our results showed that in the upper airways of patients with mild, non-severe, or severe COVID-19 manifestations, the IFN- α, - β and - λ are expressed in the same manner as in controls. However, in blood samples their expression was downregulated in all groups. Univariate linear models with interferons as predictors to evaluate clinical-biological parameters highlighted that the main clinical-biological relations were found when testing: FiO2, Lymphocyte values and virus load. Furthermore, the multivariate models confirmed that quantifications of interferons during COVID-19 are good biological markers for tracking COVID-19 pathophysiology.
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Project description:Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Without approved antiviral therapeutics or vaccines to this ongoing global threat, type I and type III interferons (IFNs) are currently being evaluated for their efficacy. Both the role of IFNs and the use of recombinant IFNs in two related, highly pathogenic coronaviruses, SARS-CoV and MERS-CoV, have been controversial in terms of their protective effects in the host. In this review, we describe the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses and discuss the potential use of IFNs as a treatment strategy for COVID-19.
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Project description:Human metapneumovirus (HMPV) is an important cause of acute lower respiratory infection in children and adults worldwide. There are four genetic subgroups of HMPV and both neutralizing antibodies and T cells contribute to protection. However, little is known about mechanisms of pathogenesis and most published work is based on a few extensively passaged, laboratory-adapted strains of HMPV. In this study, we isolated and characterized a panel of low passage HMPV clinical isolates representing all four genetic subgroups. The clinical isolates exhibited lower levels of in vitro replication compared to a lab-adapted strain. We compared disease phenotypes using a well-established mouse model. Several virulent isolates caused severe weight loss, lung pathology, airway dysfunction, and fatal disease in mice, which was confirmed in three inbred mouse strains. Disease severity did not correlate with lung viral titer, as virulent strains exhibited restricted replication in the lower airway. Virulent HMPV isolates were associated with markedly increased proinflammatory cytokine production and neutrophil influx; however, depletion of neutrophils or genetic ablation of inflammasome components did not reverse disease. Virulent clinical isolates induced markedly increased type I and type III interferon (IFN) secretion in vitro and in vivo. STAT1/2-deficient mice lacking both type I and type III IFN signaling showed reduced disease severity and increased lung viral replication. Inhibition of type I IFN signaling using a blocking antibody or genetic ablation of the type I IFN receptor reduced pathology with minimal effect on viral replication. Conversely, blockade of type III IFN signaling with a neutralizing antibody or genetic ablation of the IFN-lambda receptor had no effect on pathogenesis but restored viral replication. Collectively, these results demonstrate distinct roles for type I and type III IFN in HMPV pathogenesis and immunity.
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Project description:Among the many activities attributed to the type I interferon (IFN) multigene family, their roles as mediators of the antiviral immune response have emerged as important components of the host response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Viruses likewise have evolved multiple immune evasion strategies to circumvent the host immune response and promote virus propagation and dissemination. Therefore, a thorough characterization of host-virus interactions is essential to understand SARS-CoV-2 pathogenesis. Here, we summarize the virus-mediated evasion of the IFN responses and the viral functions involved, the genetic basis of IFN production in SARS-CoV-2 infection and the progress of clinical trials designed to utilize type I IFN as a potential therapeutic tool.
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Project description:Type 1 interferons have a broad antiviral activity in vitro and are currently evaluated in a clinical trial to treat MERS-CoV. In this review, we discuss preliminary data concerning the potential activity of type 1 interferons on SARS-CoV-2, and the relevance of evaluating these molecules in clinical trials for the treatment of COVID-19.
| S-EPMC7138382 | biostudies-literature
Project description:Type I (IFN-α/β) and type III (IFN-λ) interferons (IFNs) exert shared antiviral activities through distinct receptors. However, their relative importance for antiviral protection of different organ systems against specific viruses remains to be fully explored. We used mouse strains deficient in type-specific IFN signaling, STAT1 and Rag2 to dissect distinct and overlapping contributions of type I and type III IFNs to protection against homologous murine (EW-RV strain) and heterologous (non-murine) simian (RRV strain) rotavirus infections in suckling mice. Experiments demonstrated that murine EW-RV is insensitive to the action of both types of IFNs, and that timely viral clearance depends upon adaptive immune responses. In contrast, both type I and type III IFNs can control replication of the heterologous simian RRV in the gastrointestinal (GI) tract, and they cooperate to limit extra-intestinal simian RRV replication. Surprisingly, intestinal epithelial cells were sensitive to both IFN types in neonatal mice, although their responsiveness to type I, but not type III IFNs, diminished in adult mice, revealing an unexpected age-dependent change in specific contribution of type I versus type III IFNs to antiviral defenses in the GI tract. Transcriptional analysis revealed that intestinal antiviral responses to RV are triggered through either type of IFN receptor, and are greatly diminished when receptors for both IFN types are lacking. These results also demonstrate a murine host-specific resistance to IFN-mediated antiviral effects by murine EW-RV, but the retention of host efficacy through the cooperative action by type I and type III IFNs in restricting heterologous simian RRV growth and systemic replication in suckling mice. Collectively, our findings revealed a well-orchestrated spatial and temporal tuning of innate antiviral responses in the intestinal tract where two types of IFNs through distinct patterns of their expression and distinct but overlapping sets of target cells coordinately regulate antiviral defenses against heterologous or homologous rotaviruses with substantially different effectiveness.
| S-EPMC4851417 | biostudies-literature
Project description:Interferons were repeatedly used in the therapy of COVID-19 due to their antiviral effects. Three recently published randomized controlled clinical phase III trials (WHO SOLIDARITY, ACTT-3, and SPRINTER) missed their primary objectives, i.e., a significant therapeutic effect of interferons was not demonstrated in these studies. In only one randomized controlled phase III trial (TOGETHER), a significant reduction in the hospitalization rate was revealed. Our study analyzes these findings, gives possible explanations for the failure of interferons, provides a proposal on how these agents could be successfully used, and also highlights the limitations of their employment in COVID-19. Interferons are apparently beneficial only if the patients are in the early stage of this disease and when they are usually not hospitalized, i.e., if the patients do not require oxygen support and/or if corticosteroids are not yet indicated. Furthermore, a higher dosage than the one used in the long-term treatment of multiple sclerosis with interferon beta or of chronic viral hepatitis with interferon alpha or lambda should be employed to achieve a better therapeutic effect in COVID-19.
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Project description:The interferon (IFN)-λ family of type III cytokines includes the closely related interleukin (IL)-28A (IFN-λ2), IL-28B (IFN-λ3), and IL-29 (IFN-λ1). They signal through the Janus kinases (JAK)-signal transducers and activators of transcription pathway and promote an antiviral state by the induction of expression of several interferon-stimulated genes (ISGs). Contrary to type I IFNs, the effect of IFN-λ cytokines is largely limited to epithelial cells due to the restricted pattern of expression of their specific receptor. Several genome-wide association studies have established a strong correlation between polymorphism in the region of IL-28B gene (encoding for IFN-λ3) and both spontaneous and therapeutic IFN-mediated clearance of hepatitis C virus (HCV) infection, but the mechanism(s) underlying this enhanced viral clearance are not fully understood. IFN-λ3 directly inhibits HCV replication, and in vitro studies suggest that polymorphism in the IFN-λ3 and its recently identified overlapping IFN-λ4 govern the pattern of ISGs induced upon HCV infection of hepatocytes. IFN-λ can also be produced by dendritic cells, and apart from its antiviral action on hepatocytes, it can regulate the inflammatory response of monocytes/macrophages, thus acting at the interface between innate and adaptive immunity. Here, we review the current state of knowledge about the role of IFN-λ cytokines in mediating and regulating the immune response during acute and chronic HCV infections.
| S-EPMC5179541 | biostudies-literature
Project description:Children with the new coronavirus disease 2019 (COVID-19) have milder symptoms and a better prognosis than adult patients. Several investigations assessed type I, II, and III interferon (IFN) signatures in SARS-CoV-2 infected adults, however no data are available for pediatric patients. TRIM28 and SETDB1 regulate the transcription of multiple genes involved in the immune response as well as of human endogenous retroviruses (HERVs). Exogenous viral infections can trigger the activation of HERVs, which in turn can induce inflammatory and immune reactions. Despite the potential cross-talks between SARS-CoV-2 infection and TRIM28, SETDB1, and HERVs, information on their expressions in COVID-19 patients is lacking. We assessed, through a PCR real time Taqman amplification assay, the transcription levels of six IFN-I stimulated genes, IFN-II and three of its sensitive genes, three IFN-lIIs, as well as of TRIM28, SETDB1, pol genes of HERV-H, -K, and -W families, and of env genes of Syncytin (SYN)1, SYN2, and multiple sclerosis-associated retrovirus (MRSV) in peripheral blood from COVID-19 children and in control uninfected subjects. Higher expression levels of IFN-I and IFN-II inducible genes were observed in 36 COVID-19 children with mild or moderate disease as compared to uninfected controls, whereas their concentrations decreased in 17 children with severe disease and in 11 with multisystem inflammatory syndrome (MIS-C). Similar findings were found for the expression of TRIM-28, SETDB1, and every HERV gene. Positive correlations emerged between the transcriptional levels of type I and II IFNs, TRIM28, SETDB1, and HERVs in COVID-19 patients. IFN-III expressions were comparable in each group of subjects. This preserved induction of IFN-λs could contribute to the better control of the infection in children as compared to adults, in whom IFN-III deficiency has been reported. The upregulation of IFN-I, IFN-II, TRIM28, SETDB1, and HERVs in children with mild symptoms, their declines in severe cases or with MIS-C, and the positive correlations of their transcription in SARS-CoV-2-infected children suggest that they may play important roles in conditioning the evolution of the infection.
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