The Suppressor of Cytokine Signalling family of proteins and their potential impact on COVID‐19 disease progression (original) (raw)
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Therapeutic Approaches for COVID-19 Based on the Dynamics of Interferon-mediated Immune Responses
As the outbreak of COVID-19 has accelerated, an urgent need for finding strategies to combat the virus is growing. Thus, gaining more knowledge on the pathogenicity mechanisms of SARS-CoV-2, the causing agent of COVID-19, and its interaction with the immune system is of utmost importance. Although this novel virus is not well known yet, its structural and genetic similarity with SARS-CoV as well as the comparable pattern of age-mortality relations suggest that the previous findings on SARS can be applicable for COVID-19. Therefore, a systems biology study was conducted to investigate the most important signaling pathways activated by the virus. The results were then validated through a literature review on COVID-19 and the other closely related viruses, SARS and MERS. Interferons have shown to play a crucial role in the defense against coronavirus diseases. CoV can impede the interferon induction in humans. Moreover, STAT1, a key protein in the interferon-mediated immune response, i...
SARS-CoV-2 Non-Structural Proteins and Their Roles in Host Immune Evasion
Viruses, 2022
Coronavirus disease 2019 (COVID-19) has caused an unprecedented global crisis and continues to threaten public health. The etiological agent of this devastating pandemic outbreak is the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). COVID-19 is characterized by delayed immune responses, followed by exaggerated inflammatory responses. It is well-established that the interferon (IFN) and JAK/STAT signaling pathways constitute the first line of defense against viral and bacterial infections. To achieve viral replication, numerous viruses are able to antagonize or hijack these signaling pathways to attain productive infection, including SARS-CoV-2. Multiple studies document the roles of several non-structural proteins (NSPs) of SARS-CoV-2 that facilitate the establishment of viral replication in host cells via immune escape. In this review, we summarize and highlight the functions and characteristics of SARS-CoV-2 NSPs that confer host immune evasion. The molecular mechanisms mediating immune evasion and the related potential therapeutic strategies for controlling the COVID-19 pandemic are also discussed.
Viruses
Coronaviruses (CoVs) have caused several global outbreaks with relatively high mortality rates, including Middle East Respiratory Syndrome coronavirus (MERS)-CoV, which emerged in 2012, and Severe Acute Respiratory Syndrome (SARS)-CoV-1, which appeared in 2002. The recent emergence of SARS-CoV-2 highlights the need for immediate and greater understanding of the immune evasion mechanisms used by CoVs. Interferon (IFN)-α is the body’s natural antiviral agent, but its Janus kinase/signal transducer and activators of transcription (JAK/STAT) signalling pathway is often antagonized by viruses, thereby preventing the upregulation of essential IFN stimulated genes (ISGs). Therapeutic IFN-α has disappointingly weak clinical responses in MERS-CoV and SARS-CoV-1 infected patients, indicating that these CoVs inhibit the IFN-α JAK/STAT pathway. Here we show that in lung alveolar A549 epithelial cells expression of MERS-CoV-nsp2 and SARS-CoV-1-nsp14, but not MERS-CoV-nsp5, increased basal levels...
Therapeutic Approaches for COVID-19 Based on the Interferon-Mediated Immune Responses
Current Signal Transduction Therapy, 2021
Background: As the outbreak of COVID-19 has accelerated, an urgent need for finding strategies to combat the virus is growing. Thus, gaining more knowledge on the pathogenicity mechanism of SARS-CoV-2, i.e. the causing agent of COVID-19, and its interaction with the immune system is of utmost importance. Although this novel virus is not well known yet, its structural and genetic similarity with SARS-CoV as well as the comparable pattern of age-mortality relations suggest that some previous findings on SARS could be applicable for COVID-19. Objective: The aim of this study was to investigate the most important signaling pathways activated by coronaviruses to better understand the viral pathogenesis and host immune responses. Method: Here, a systems biology study was conducted on a SARS database. It was followed by a literature review on the cognate subject. Results: It was proved that interferons may possess a crucial role in the defense against coronavirus diseases. The literature s...
Journal of Interferon & Cytokine Research
Flaviviruses cause significant human diseases putting more than 400 million people at risk annually worldwide. Because of migration and improved transportation, these viruses can be found on all continents (except Antarctica). Although a majority of the viruses are endemic in the tropics, a few [West Nile virus (WNV) and tick-borne encephalitis virus (TBEV)] have shown endemicity in Europe and North America. Currently, there are vaccines for the Yellow fever virus, Japanese encephalitis virus, and TBEV, but there is no effective vaccine and/or therapy against all other flaviviruses. Although there are intensive efforts to develop vaccines for Zika viruses, dengue viruses, and WNVs, there is the need for alternative or parallel antiviral therapeutic approaches. Suppressors of cytokine signaling (SOCS) and protein inhibitors of activated signal transducer and activator of transcription (STATs; PIAS), both regulatory proteins of the Janus kinase/STAT signaling pathway, have been explored as therapeutic targets in herpes simplex and vaccinia viruses, as well as in cancer therapy. In this review, we briefly describe the function of SOCS and PIAS and their therapeutic potential in flaviviral infections.
Influenza A Virus Inhibits Type I IFN Signaling via NF-κB-Dependent Induction of SOCS-3 Expression
PLoS Pathogens, 2008
The type I interferon (IFN) system is a first line of defense against viral infections. Viruses have developed various mechanisms to counteract this response. So far, the interferon antagonistic activity of influenza A viruses was mainly observed on the level of IFNb gene induction via action of the viral non-structural protein 1 (NS1). Here we present data indicating that influenza A viruses not only suppress IFNb gene induction but also inhibit type I IFN signaling through a mechanism involving induction of the suppressor of cytokine signaling-3 (SOCS-3) protein. Our study was based on the observation that in cells that were infected with influenza A virus and subsequently stimulated with IFNa/b, phosphorylation of the signal transducer and activator of transcription protein 1 (STAT1) was strongly reduced. This impaired STAT1 activation was not due to the action of viral proteins but rather appeared to be induced by accumulation of viral 59 triphosphate RNA in the cell. SOCS proteins are potent endogenous inhibitors of Janus kinase (JAK)/STAT signaling. Closer examination revealed that SOCS-3 but not SOCS-1 mRNA levels increase in an RNA-and nuclear factor kappa B (NF-kB)-dependent but type I IFN-independent manner early in the viral replication cycle. This direct viral induction of SOCS-3 mRNA and protein expression appears to be relevant for suppression of the antiviral response since in SOCS-3 deficient cells a sustained phosphorylation of STAT1 correlated with elevated expression of type I IFN-dependent genes. As a consequence, progeny virus titers were reduced in SOCS-3 deficient cells or in cells were SOCS-3 expression was knocked-down by siRNA. These data provide the first evidence that influenza A viruses suppress type I IFN signaling on the level of JAK/STAT activation. The inhibitory effect is at least in part due to the induction of SOCS-3 gene expression, which results in an impaired antiviral response.
2020
COVID-19, a pandemic affecting virus, which is caused by the current SARS-CoV2 coronavirus. The present research is performed on anti virus and immune-modulating therapies. Cytokine storms are the toxic drivers and mortality caused by various human viral infections. In addition, the intensity was linked to an elevated risk of acute respiratory failure, myocardial injury, and mortality in SARS-CoV-2-infected patients. The Janus kinase (JAK) therapeutic inhibitor class showed significant clinical benefits in anti-inflammatory and anti-viral effects. Among them, filgotinib has been approved as an active JAK inhibitor by decreasing biomarkers with main immune reaction functions and markers supporting matrix-degradation, angiogenesis, leukocyte adhesion, and recruitment in both research trials. In this study, we tried to get an insight into the choice of this drug in controlling the jack, to treat Covid 19 using drug design methods will be discussed.
2020
The COVID-19 is a pandemic caused by SARS-CoV-2 virus has presented a striking challenge into the health care systems (HCSs) around the World and currently is the source of public health concern globally. The treatment of this disease has remained challenging as there are no proven effective vaccines or therapeutic agents against the virus. Cytokine Storm Syndrome (CSS) is an unregulated inflammatory process response arising from immune effector cells (IECs) releasing proinflammatory cytokines. That occurs as a result of the overproduction of pro-inflammatory cytokines. CSS is a frequently occurring feature of severe infections with COVID-19 pneumonia and violent inflammatory immune response (VIIR) is stimulated by cytokine storm syndrome (CSS) is misleading into the development of symptoms such as fever, throat infections, headaches, dizziness, fatigue, cardiomyopathy, lung injury, acute respiratory distress, multiple organ failure, and subsequent death of the majority of the patients. The new therapeutic strategies under investigation are targeting to the overactive cytokine response (OCR) within the anti-cytokine therapies and immu-nosuppressive agents. CSS helps to down-regulate and dampen the aberrant pro-inflammatory response of the host and may bring an understanding and insights into the treatment of the SARS-CoV-2 virus. In this review, we have outlined and discussed the different types of cytokines therapies and their mechanism of actions. Currently, being explored and evaluated those that are not yet evaluated for their efficacy and safety in the treatment of COVID-19 and associated with the cytokine storm syndrome (CSS). We suggested that the clinical trials should be initiated for those are new therapies that are not yet explored to evaluate their efficacy and safety in the management and treatment of COVID-19 pneumonia and the SARS-CoV-2.
The roles of signaling pathways in SARS-CoV-2 infection; lessons learned from SARS-CoV and MERS-CoV
Archives of Virology
The number of descriptions of emerging viruses has grown at an unprecedented rate since the beginning of the 21 st century. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is the third highly pathogenic coronavirus that has introduced itself into the human population in the current era, after SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Molecular and cellular studies of the pathogenesis of this novel coronavirus are still in the early stages of research; however, based on similarities of SARS-CoV-2 to other coronaviruses, it can be hypothesized that the NF-κB, cytokine regulation, ERK, and TNF-α signaling pathways are the likely causes of inflammation at the onset of COVID-19. Several drugs have been prescribed and used to alleviate the adverse effects of these inflammatory cellular signaling pathways, and these might be beneficial for developing novel therapeutic modalities against COVID-19. In this review, we briefly summarize alterations of cellular signaling pathways that are associated with coronavirus infection, particularly SARS-CoV and MERS-CoV, and tabulate the therapeutic agents that are currently approved for treating other human diseases.