The role of IL-1 family of cytokines and receptors in pathogenesis of COVID-19

A global pandemic has erupted as a result of the new brand coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pandemic has been consociated with widespread mortality worldwide. The antiviral immune response is an imperative factor in confronting the recent coronavirus disease 2019 (COVID-19) infections. Meantime, cytokines recognize as crucial components in guiding the appropriate immune pathways in the restraining and eradication of the virus. Moreover, SARS-CoV-2 can induce uncontrolled inflammatory responses characterized by hyper-inflammatory cytokine production, which causes cytokine storm and acute respiratory distress syndrome (ARDS). As excessive inflammatory responses are contributed to the severe stage of the COVID-19 disease, therefore, the pro-inflammatory cytokines are regarded as the Achilles heel during COVID-19 infection. Among these cytokines, interleukin (IL-) 1 family cytokines (IL-1, IL-18, IL-33, IL-36, IL-37, and IL-38) appear to have a strong inflammatory role in severe COVID-19. Hence, understanding the underlying inflammatory mechanism of these cytokines during infection is critical for reducing the symptoms and severity of the disease. Here, the possible mechanisms and pathways involved in inflammatory immune responses are discussed.

     

Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review

Severe Acute Respiratory Syndrome related to Coronavirus-2 (SARS-CoV-2), coronavirus disease-2019 (COVID-19) may cause severe illness in 20% of patients. This may be in part due to an uncontrolled immune-response to SARS-CoV-2 infection triggering a systemic hyperinflammatory response, the so-called “cytokine storm”. The reduction of this inflammatory immune-response could be considered as a potential therapeutic target against severe COVID-19. The relationship between inflammation and clot activation must also be considered. Furthermore, we must keep in mind that currently, no specific antiviral treatment is available for SARS-CoV-2. While moderate-severe forms need in-hospital surveillance plus antivirals and/or hydroxychloroquine; in severe and life-threating subsets a high intensity anti-inflammatory and immunomodulatory therapy could be a therapeutic option. However, right data on the effectiveness of different immunomodulating drugs are scarce. Herein, we discuss the pathogenesis and the possible role played by drugs such as: antimalarials, anti-IL6, anti-IL-1, calcineurin and JAK inhibitors, corticosteroids, immunoglobulins, heparins, angiotensin-converting enzyme agonists and statins in severe COVID-19.     

Discriminating promiscuous from target-specific autoantibodies in COVID-19

Diverse autoantibodies were suggested to contribute to severe outcomes of COVID-19, but their functional implications are largely unclear. ACE2, the SARS-CoV-2 receptor and a key regulator of blood pressure, was described to be one of many targets of autoantibodies in COVID-19. ACE2 in its soluble form (sACE2) is highly elevated in the blood of critically ill patients, raising the question of whether sACE2:spike complexes induce ACE2 reactivity. Screening 247 COVID-19 patients, we observed elevated sACE2 and anti-ACE2 IgG that were poorly correlated. Interestingly, levels of IgGs recognizing ACE2, IFNα2, and CD26 strongly correlated in severe COVID-19, with 15% of sera showing polyreactivity versus 4.1% exhibiting target-directed autoimmunity. Promiscuous autoantibodies failed to impair the activity of ACE2 and IFNα2, while only specific anti-IFNα2 IgG compromised cytokine function. Our study suggests that the detection of autoantibodies in COVID-19 is often attributed to a promiscuous reactivity, potentially misinterpreted as target-specific autoimmunity with functional impact.     

Roles of Type I and III Interferons in COVID-19

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I and III interferon (IFN) responses act as the first line of defense against viral infection and are activated by the recognition of viruses by infected cells and innate immune cells. Dysregulation of host IFN responses has been known to be associated with severe disease progression in COVID-19 patients. However, the reported results are controversial and the roles of IFN responses in COVID-19 need to be investigated further. In the absence of a highly efficacious antiviral drug, clinical studies have evaluated recombinant type I and III IFNs, as they have been successfully used for the treatment of infections caused by two other epidemic coronaviruses, SARS-CoV-1 and Middle East respiratory syndrome (MERS)-CoV. In this review, we describe the strategies by which SARS-CoV-2 evades IFN responses and the dysregulation of host IFN responses in COVID-19 patients. In addition, we discuss the therapeutic potential of type I and III IFNs in COVID-19.     

A review of COVID-19 convalescent plasma use in COVID-19 with focus on proof of efficacy

Convalescent plasma (CP) therapy is rapidly becoming an established consideration in the treatment of COVID-19 patients though there is a need to critically review this area for proof of efficacy. Neutralizing antibodies (NAb) present in CP generated in response to SARS-CoV-2 infection directed against the receptor-binding domain (RBD) of the spike protein are considered to play main role in viral clearance. CP infusion may also help in the modulation of immune response by its immunomodulatory effect. The FDA allows for administration of CP to COVID-19 patients. The present published literature in COVID-19 is limited to case series and randomised controlled trial where plasma therapy was used in moderate, severe and critically ill patients. Though multiple uncertainties exist regarding to its efficacy, appropriate donor selection and NAb titres, the efficacy data of CP use inCOVID-19 is limited having shown hope with early and severe to critically ill COVID-19 patients.

     

TRIM10 binds to IFN-α/β receptor 1 to negatively regulate type I IFN signal transduction

The type I interferon (IFN-I) system is important for antiviral and anticancer immunity. Prolonged activation of IFN/JAK/STAT signaling is closely associated with autoimmune diseases. TRIM10 dysfunction may be associated closely with certain autoimmune disorders. Here, we observed that the serum TRIM10 protein level is lower in patients with systemic lupus erythematosus than in healthy control subjects. We speculated the possible involvement of TRIM10-induced modulation of the IFN/JAK/STAT signaling pathway in systemic lupus erythematosus. In line with our hypothesis, TRIM10 inhibited the activation of JAK/STAT signaling pathway triggered by various stimuli. TRIM10 restricted the IFN-I/JAK/STAT signaling pathway, which was independent of its E3 ligase activity. Mechanistically, TRIM10 interacted with the intracellular domain of IFNAR1 and blocked the association of IFNAR1 with TYK2. These data suggest the possible TRIM10 suppresses IFN/JAK/STAT signaling pathway through blocking the interaction between IFNAR1 and TYK2. Targeting TRIM10 is a potential strategy for treating autoimmune diseases.     

A network pharmacology based approach for predicting active ingredients and potential mechanism of Lianhuaqingwen capsule in treating COVID-19

The outbreak of severe respiratory disease caused by SARS-CoV-2 has led to millions of infections and raised global health concerns. Lianhuaqingwen capsule (LHQW-C), a traditional Chinese medicine (TCM) formula widely used for respiratory diseases, shows therapeutic efficacy in the application of coronavirus disease 2019 (COVID-19). However, the active ingredients, drug targets, and the therapeutic mechanisms of LHQW-C in treating COVID-19 are poorly understood. In this study, an integrating network pharmacology approach including pharmacokinetic screening, target prediction (targets of the host and targets from the SARS-CoV-2), network analysis, GO enrichment analysis, KEGG pathway enrichment analysis, and virtual docking were conducted. Finally, 158 active ingredients in LHQW-C were screen out, and 49 targets were predicted. GO function analysis revealed that these targets were associated with inflammatory response, oxidative stress reaction, and other biological processes. KEGG enrichment analysis indicated that the targets of LHQW-C were highly enriched to several immune response-related and inflammation-related pathways, including the IL-17 signaling pathway, TNF signaling pathway, NF-kappa B signaling pathway, and Th17 cell differentiation. Moreover, four key components (quercetin, luteolin, wogonin, and kaempferol) showed a high binding affinity with SARS-CoV-2 3-chymotrypsin-like protease (3CL pro). The study indicates that some anti-inflammatory ingredients in LHQW-C probably modulate the inflammatory response in severely ill patients with COVID-19.     

Development of protective immunity against cutaneous leishmaniasis is dependent on STAT1-mediated IFN signaling pathway

Although STAT1-dependent signaling mediates biological functions of IFN-alpha/beta and IFN-gamma, recent reports indicate that STAT1-independent IFN signaling also regulates expression of several genes. To determine the roles of STAT1-dependent and -independent IFN signaling in the regulation of immunity during cutaneous leishmaniasis, we studied the course of Leishmania major infection in resistant C57BL/6 mice lacking the STAT1 gene. While L. major-infected STAT1(+/+) mice resolved their lesions, STAT1(-/-) mice developed large lesions containing significantly more parasites. Moreover, the inability of STAT1(-/-) mice to control L. major infection was due to the lack of Th1 development associated with reduced production of IL-12, IFN-gamma and nitric oxide. Although STAT1(-/-) mice produced more IL-4 and total IgE than STAT1(+/+) mice later during infection, these differences were not significant. Nevertheless, at these time points lymph node cells from STAT1(-/-) mice produced significantly more IL-10. Finally, STAT1(-/-) mice were also susceptible to low dose L. major infection. Thesefindings demonstrate that STAT1-mediated IFN signaling is indispensable for the development of protective immunity against cutaneous L. major infection. Moreover, they also suggest that the protective role of STAT1-mediated signaling is due to its ability to induce Th1 development during infection with this parasite.     

Tofacitinib therapy intercepts macrophage metabolic reprogramming instigated by SARS-CoV-2 Spike protein

The molecular mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein was characterized to identify novel therapies. The impact of tofacitinib, IL-6R Ab, or TNFi therapy was determined on Spike protein or LPS/IFN-γ-induced signaling, inflammation, and metabolic reprogramming in MΦs and/or rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS). ACE2 frequency was markedly expanded in MΦs compared to T cells and RA FLS. Tofacitinib suppresses Spike protein potentiated STAT1 signaling, whereas this function was unchanged by TNFi. Tofacitinib impairs IL-6/IFN/LPS-induced STAT1 and STAT3 phosphorylation in RA MΦs and FLS. Interestingly, tofacitinib had a broader inhibitory effect on the monokines, glycolytic regulators, or oxidative metabolites compared to IL-6R Ab and TNFi in Spike-protein-activated MΦs. In contrast, all three therapies disrupted IFN-α and IFN-β secretion in response to Spike protein; nonetheless, the IFN-γ was only curtailed by tofacitinib or IL-6R Ab. While tofacitinib counteracted MΦ metabolic rewiring instigated by Spike protein, it was inconsequential on the glycolysis expansion mediated via HK2 and/or LDHA in the activated RA MΦ and FLS. Nevertheless, the potentiated inflammatory response and the diminished oxidative phosphorylation modulated by Spike protein and/or LPS/IFN-γ stimulation in MΦs or RA FLS were reversed by tofacitinib. In conclusion, tofacitinib suppresses MΦ inflammation and immunometabolism triggered by Spike protein and may provide a promising strategy for COVID-19 patients.     

Using IL-2R/lymphocytes for predicting the clinical progression of patients with COVID-19

Effective laboratory markers for the estimation of disease severity and predicting the clinical progression of coronavirus disease-2019 (COVID-19) is urgently needed. Laboratory tests, including blood routine, cytokine profiles and infection markers, were collected from 389 confirmed COVID-19 patients. The included patients were classified into mild (n = 168), severe (n = 169) and critical groups (n = 52). The leukocytes, neutrophils, infection biomarkers [such as C-reactive protein (CRP), procalcitonin (PCT) and ferritin] and the concentrations of cytokines [interleukin (IL)-2R, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α] were significantly increased, while lymphocytes were significantly decreased with increased severity of illness. The amount of IL-2R was positively correlated with the other cytokines and negatively correlated with lymphocyte number. The ratio of IL-2R to lymphocytes was found to be remarkably increased in severe and critical patients. IL-2R/lymphocytes were superior compared with other markers for the identification of COVID-19 with critical illness, not only from mild but also from severe illness. Moreover, the cytokine profiles and IL-2R/lymphocytes were significantly decreased in recovered patients, but further increased in disease-deteriorated patients, which might be correlated with the outcome of COVID-19. Lymphopenia and increased levels of cytokines were closely associated with disease severity. The IL-2R/lymphocyte was a prominent biomarker for early identification of severe COVID-19 and predicting the clinical progression of the disease.     

Tocilizumab treatment in COVID-19: A single center experience

Tocilizumab (TCZ), a monoclonal antibody against interleukin-6 (IL-6), emerged as an alternative treatment for COVID-19 patients with a risk of cytokine storms recently. In the present study, we aimed to discuss the treatment response of TCZ therapy in COVID-19 infected patients. The demographic, treatment, laboratory parameters of C-reactive protein (CRP) and IL-6 before and after TCZ therapy and clinical outcome in the 15 COVID-19 patients were retrospectively assessed. Totally 15 patients with COVID-19 were included in this study. Two of them were moderately ill, six were seriously ill and seven were critically ill. The TCZ was used in combination with methylprednisolone in eight patients. Five patients received the TCZ administration twice or more. Although TCZ treatment ameliorated the increased CRP in all patients rapidly, for the four critically ill patients who received an only single dose of TCZ, three of them (No. 1, 2, and 3) still dead and the CRP level in the rest one patient (No. 7) failed to return to normal range with a clinical outcome of disease aggravation. Serum IL-6 level tended to further spiked firstly and then decreased after TCZ therapy in 10 patients. A persistent and dramatic increase of IL-6 was observed in these four patients who failed treatment. TCZ appears to be an effective treatment option in COVID-19 patients with a risk of cytokine storms. And for these critically ill patients with elevated IL-6, the repeated dose of the TCZ is recommended.     

STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the overexpression of IFN‐α. IFN‐α induces autophagy via the JAK1‐STAT1 signaling pathway, contributing to the pathogenesis of SLE. Recent studies reported that B cells from patients with SLE and NZB/W F1 mice had enhanced autophagy activity; however, the mechanism still remains unknown. Here, we show that the protein tyrosine phosphatase STS‐1 (suppressor of T‐cell receptor signaling 1) was significantly overexpressed in B cells from patients with SLE and MRL/lpr mice. Notably, STS‐1 promoted IFN‐α‐induced autophagy in B cells by enhancing the JAK1‐STAT1 signaling activation. STS‐1 inhibited the phosphorylation of the E3 ubiquitin protein ligase c‐cbl, and subsequently promoted IFN‐α‐induced phosphorylation of tyrosine kinase 2, leading to JAK1‐STAT1 signaling activation. Furthermore, STAT1 and JAK1 inhibitors blocked the IFN‐α‐induced autophagy promoted by STS‐1, indicating that STS‐1 promotes IFN‐α‐induced autophagy via the JAK1‐STAT1 signaling. Our results demonstrate the importance of STS‐1 in regulating IFN‐α‐induced autophagy in B cells, and this could be used as a therapeutic approach to treat SLE.     

The role of type I interferon in the treatment of COVID-19

Although significant research has been done to find effective drugs against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), no definite effective drug exists. Thus, research has now shifted towards immunomodulatory agents other than antivirals. In this review, we aim to describe the latest findings on the role of type I interferon (IFN)-mediated innate antiviral response against SARS-CoV-2 and discuss the use of IFNs as a medication for COVID-19. A growing body of evidence has indicated a promoting active but delayed IFNs response to SARS-CoV-2 and Middle East respiratory syndrome coronavirus in infected bronchial epithelial cells. Studies have demonstrated that IFNs' administration before the viral peak and the inflammatory phase of disease could offer a highly protective effect. However, IFNs' treatment during the inflammatory and severe stages of the disease causes immunopathology and long-lasting harm for patients. Therefore, it is critical to note the best time window for IFNs' administration. Further investigation of the clinical effectiveness of interferon for patients with mild to severe COVID-19 and its optimal timing and route of administration can be beneficial in finding a safe and effective antiviral therapy for the COVID-19 disease.     

SOCS和IFN对JAK/STAT活化的影响和意义

信号抑制因子(SOCS)是在细胞因子诱导下依赖JAK/STAT通路的信号传导而产生的,继而抑制细胞因子的信号传导,因此SOCS蛋白质被认为可以形成局部经典负反馈回路.IFN是由辅助性T细胞Ⅰ类亚群和自然杀伤细胞等分泌的一种细胞因子,具有多种免疫调节功能.在炎症反应中IFN首先激活JAK,然后再活化与之相结合的STATI和STAT3,从而引起iNOS诱生型一氧化氮表达增强而诱发炎症反应,而IFN在诱导细胞的抗病毒和抗生长反应中也起关键作用.IFN可正向调节SOCS的表达,但是SOCS的过度表达又可以抑制IFN受体的磷酸化及STAT1、STAT3的活化.