key: cord-317820-od9l7p1r
authors: Goker Bagca, Bakiye; Biray Avci, Cigir
title: Overview of the COVID-19 and JAK/STAT Pathway Inhibition: Ruxolitinib Perspective
date: 2020-06-20
journal: Cytokine Growth Factor Rev
DOI: 10.1016/j.cytogfr.2020.06.013
sha: 
doc_id: 317820
cord_uid: od9l7p1r

Ruxolitinib is the first approved JAK1 and JAK2 inhibitor. It inhibits the JAK / STAT pathway which is one of the main cellular signaling pathways especially regulates inflammatory response. COVID-19 is an urgent pandemic situation caused by SARS-CoV-2 infection. This review firstly presents an overview of SARS-CoV-2 and COVID-19, and then it focuses on the potential efficacy of ruxolitinib in this infection. The possible targets of ruxolitinib are determined by using genetic alterations that have been reported in COVID-19 patients. The potential effectiveness of ruxolitinib is suggested by evaluating the interactions of these potential targets which are directly affected by the ruxolitinib or JAK/STAT pathway.

The virus, which is the cause of the COVID-19 was named as Severe Acute Respiratory Syndromerelated Coronavirus (SARS-CoV-2) by Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (Figure 1a) . SARS-CoV-2 is a betacoronavirus and it is in the Coronaviridae family along with two other species that infect humans, SARS-CoV, and MERS-CoV [3] .

The genomic structure of the virus is a positive-sense, single-stranded RNA which is approximately 30 kb (29903 nucleotides). The viral RNA is packaged by nucleocapsid proteins and this structure is surrounded by a bilayer lipid corona structure which includes membrane, envelope, and spike proteins (Figure 1b) The S protein of virion binds to the ACE2 receptor of the cell that will be infected by the virus (Figure 1c) . In the process following the binding, it is suggested that proteases especially TMPRSS2, on the surface of the host cell can strengthen binding and trigger receptor-mediated endocytosis by causing conformational changes in the S glycoprotein [5] . The early endosome carrying the virion matures towards the late endosome during vesicular traffic process and the gradual increase in the endosomal lumen acidity causes the release of the viral genome to the cytoplasm [7] . Firstly, ORF1ab is translated using the viral RNA, and its cleavage forms RNA-dependent RNA polymerase which involved in both replication and transcription of structural proteins. Using these transcripts, cytoplasmic ribosomes translate the nucleocapsid protein, and ER-bound ribosomes translate the spike, envelope, and membrane proteins into the ER lumen. Nucleocapsid packed viral RNA is encapsulated the vesicle which carries spike, envelope, and membrane proteins on its membrane in Endoplasmic Reticulum Golgi Intermediate Compartment (ERGIC). Finally, a complete virion is released to the extracellular region by exocytosis [8] .

Symptoms J o u r n a l P r e -p r o o f SARS-CoV-2 is transmitted from human to human with droplets and from the mucosal surfaces of the nose, mouth, and eyes [9] . It is thought that the majority of the SARS-CoV-2 infected individuals are asymptomatic depending on their general health conditions and ages. Fever, dry cough, fatigue or weakness, and dyspnea are the most common (>50%); myalgia, chest oppression or pain, diarrhea, loss of or poor appetite, shortness of breath, expectoration, anorexia are common (<50% and >10%); headache, chest pain, sore throat, vomiting, loss of smell and taste are the less common (<10%) symptoms of the diagnosed cases [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] .

In addition to general symptoms and laboratory findings, chest computed tomography (CT), rapid antibody-based methods, and molecular tests including Real-Time Reverse Transcriptase-PCR are utilized for diagnosis of COVID-19 [10] .

SARS-CoV-2 was isolated from different clinical samples including upper and lower respiratory tract passages, blood, and stool. However infectious property of the live virus is not exactly defined, exclude obtained from the respiratory tract samples [21] . According to Real-Time Reverse Transcriptase-PCR test results, the positivity rate decreases in the form of bronchoalveolar lavage, sputum, throat, nasal and pharyngeal swabs, respectively [22] . Similarly, the rate is higher in the early and progressive stages of the disease than the recovery stage. The high viral load and infectious property of the respiratory samples are suggested as proof of respiratory transmission [23] .

Elderly age (≥ 65 years) is defined as the most common risk factor. Comorbidities that are hypertension, cardiovascular diseases, diabetes, chronic obstructive pulmonary diseases, malignancies, chronic kidney or hepatic diseases, asthma, or infectious diseases like as tuberculosis, and hepatitis are identified as the other following risk groups [10, 11, 13, 17, 19, 24] . Although smoking is the main risk factor of various diseases especially lung cancers, it is not certainly classified as the risk factor of COVID-19, yet [25] . It has also been noted that various genetic factors may affect the prognosis of COVID-19. For example, it has been stated that the phenotypes of HLA-B *46:01 and HLA-B*15:03 can affect the severity of infection by causing low and high binding affinity of SARS-CoV-2 to cells, respectively [26] .

Complications triggered by COVID-19 are the main factors affecting disease severity and death ratios.

The most common complication of the COVID-19 is acute respiratory distress syndrome (ARDS). It is characterized by ground-glass opacities appearance in the lungs and it results in serious respiratory failure and secondary complications including multiple organ failures related to insufficient oxygenation levels [20, 24, 27] .

Cytokine release syndrome or cytokine storm (See "4-Cytokine storm and COVID-19" section), hemophagocytic lymphohistiocytosis, and septic shock are frequently seen as complications from hyperactivation of the immune system [28] [29] [30] [31] [32] .

Guillain Barre Syndrome, hematologic disorders like autoimmune hemolytic anemia is reported during COVID-19 treatment [33, 34] . Acute cardiac, kidney, and liver injury are reported as common complications [20, 24, 27] .

Although meningitis and encephalitis are also reported as less common complications of COVID-19, other bacterial or viral co-infections are quite often and they may result in deaths [18, 35] .

Although no treatment method or drug has been approved yet, different therapy approaches are using against different symptoms of COVID-19 indication. Current treatment applications are separated into two subgroups, the first group of the treatment strategies includes antiviral drugs and immune-based therapy to overcome viral infection and the second one comprises antithrombotics, ventilation or oxygen therapies are used for secondary complications.

It is expected that antiviral drugs will be effective in COVID-19 by utilizing proven and approved mechanisms of action for other viruses. Remdesivir (GS-5734, Gilead Sciences) is an RNAdependent RNA polymerase inhibitor and used against RNA viruses like Ebolaviruses despite it has not yet been approved for any indication [36, 37] . Chloroquine (or hydroxychloroquine) is an approved antimalarial drug that increases the pH of lysosomes thusly inhibits autophagy by suppressing lysosome-autophagosome fusion [38] . This autophagy inhibitor is a part of the current COVID-19 treatment protocol because it inhibits the endocytic pathway which allows the virus entry into the cell and activation after binding to the ACE2 receptor [39] . HIV protease inhibitors are agents that have been approved for use in the treatment of HIV with the mechanism to inhibit proteins necessary to complete the life cycle of HIV [40] . It is predicted that protease inhibition performed with agents such as Lopinavir/Ritonavir (Kaletra, Abbott Laboratories) may also be effective against SARS-CoV-2 [41] .

The use of plasma (known as convalescent plasma therapy) or immune globulins from recovered individuals is being tested in clinical trials to help activate the immune system against SARS-CoV-2 in patients. Also, interferons (interferon alfa and interferon beta) are being tested at the same purpose to activate the immune system [42] . The numerous clinical studies that aim to induce adaptive immunity are maintained by different research teams [43, 44] .

It has been reported that the infection-related increase of coagulation parameters especially the D-dimer (normal range <0.5μg/ml) is directly proportional to the severity of the disease.

Coagulation abnormalities cause disseminated intravascular coagulation and it triggers venous thromboembolism and pulmonary embolism which are among the main COVID-19 related death reasons. Antithrombotic and anticoagulant drugs including heparin, warfarin, direct-acting oral anticoagulants are used against the development of coagulation and thromboembolism during the treatment process [45] .

Various genetic alterations which will be used as therapeutic targets are reported during COVID-19 infection (Figure 2) . The variations especially include inflammation and immune response regulation [10, 11, [13] [14] [15] [16] [17] 19, 24, 27, 29, 31, 32, [46] [47] [48] [49] [50] [51] [52] [53] . Upregulation and overexpression of ACE2 and TMPRSS2 may be potential reasons for virus absorption and complications in the heart, lungs, and different organs related to the nervous system [47, 54] .

As an expected result of SARS-CoV-2 infection, it was reported cytokine storm syndrome triggered by the dysregulated immunity in numerous patients. Cytokine storm is characterized by high inflammatory response including elevated levels of cytokines and immune cells which infiltrates and destroys the organs and causes lung lesions, respiratory dysfunction, multiple organ damage, and death [28] .

Cytokines are a group of immunoregulatory cell-cell communication molecules including different subtypes named chemokine (chemotaxis cytokine), interleukin (leukocyte related cytokine), lymphokine (lymphocytes-related cytokine), monokine (monocytes-related cytokine) and interferons.

Initially, although it was thought that they were secreted by only specific immune cells and effected only limited cell types, it is known that they are secreted by nonimmune cells fibroblasts or endothelial cells to respond inflammation or injury in addition to immune cells like monocytes, macrophages, B-and T-lymphocytes. The cytokines are both cause and result of the immune response and they include both pro-and anti-inflammatory molecules [55] .

Cytokines both regulate different cellular responses and their activation is controlled by molecular signaling pathways. JAK/ STAT pathway is primarily responsible for main cytokine production and immune response regulation [56] .

The Janus kinases (JAKs) and the signal transducers and activators of transcriptions (STATs) form one of the main regulator cell signaling pathway named as JAK/STAT pathway (Figure 4) . JAK nonreceptor tyrosine kinase family includes Jak1, Jak2, Jak3, and Tyrosine kinase 2 (Tyk2) proteins. Their (TAD) (carries conserved tyrosine residues which is phosphorylation sites) domains [58] . According to the message the cell regulates critical processes as proliferation, differentiation, migration, apoptosis and these responses underlie critical components of cellular homeostasis [59] .

The IL6/JAK/STAT3 signaling pathway is a specific subtype of the JAK/STAT pathway that includes IL6 which is an essential pleiotropic cytokine produced by immune cells like B cells T cells, dendritic cells, macrophages to create an immune response/ inflammation. Binding of IL6 to its specific receptor (IL6 receptor-subunit alpha IL6R) triggers a form of a heterohexameric complex with IL6 receptor subunit-β (gp130, IL6ST) and it activates the special signal pathway named as IL6/JAK/STAT3. Thusly, increased levels of IL6 trigger activation of inflammation-related downstream targets [58] .

Upregulated gene expression level or elevated serum concentration of cytokines, especially IL6 is showed that it is one of the pivotal cytokines in influenza, vaccinia, hepatitis B and C, Crimean-Congo hemorrhagic fever, and human immunodeficiency virus infections in humans and rabies, swine fever virus infections in different mammalian species [60] . Similarly, IL6 is the most remarkable cytokine in COVID-19-induced cytokine storm syndrome. Elevated serum levels of IL6 are emphasized as the main indicator of cytokine storm and poor prognosis in SARS-CoV-2 infection. The local inflammatory response also spreads to the body and causes cytokine release syndrome or cytokine storm that causes acute respiratory distress syndrome and organ damages. Different approaches which include inhibition of the elevated molecules or hyper-activated pathways and purification of the blood are suggested to overcome this hyper-inflammation situation during COVID-19 treatment [28] . The usage of the JAK/STAT pathway inhibitors and specific anti-cytokine molecules, especially anti-IL6, are the most remarkable approaches to fight this situation. The first approved JAK inhibitor is ruxolitinib, and it followed by the other JAK inhibitors that are baricitinib, upadacitinib, tofacitinib, peficitinib, and fedratinib [61] [62] [63] . There are clinical studies including baricitinib, tofacitinib, and ruxolitinib JAK inhibitors against cytokine storm caused by COVID-19. Among these, baricitinib (LY3009104, INCB028050, Olumiant, Eli Lilly) is a second JAK1 and JAK2 inhibitor is approved in 2018 for treatment of rheumatoid arthritis. Besides the antiinflammatory effects, it also inhibits endocytosis of the virus, it is suggested for COVID-19 treatments [64] . Although clinical studies have started, it has also been suggested that this molecule may make patients vulnerable to co-infection, virus reactivation, lymphocytopenia, and neutropenia, thusly it is suggested that it may not be an ideal choice [65] .

A similar situation is encountered about interleukin inhibitors also. It is reported that tocilizumab which is an approved IL6 receptor antagonist, treatment reduced cytokine release syndrome symptoms in severe patients COVID-19 [66] . On the other hand, it is also suggested that J o u r n a l P r e -p r o o f the tocilizumab application may cause poor prognosis and death by adding immunosuppression to bad clinical profiles [30] . effective treatment by overcoming the increase in cytokine levels, which is the main factor in these diseases. Therefore, ruxolitinib has started to take its place as a current subject in the treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis, and lupus erythematosus and other inflammatory diseases such as allergy and asthma [67] . Ruxolitinib also inhibits IL6/JAK/STAT3 pathway, reduces expression levels, and circulating IL6 levels [68, 69] .

There are studies involving the potential of using ruxolitinib in different viral infections due to its immune suppressor and anti-viral properties.

Ruxolitinib is used against both acute and chronic graft versus host disease which is originated from allogeneic hematopoietic stem cell transplantation with its immunosuppression features including both JAK2 and IL6 inhibitions [70] .

Hemophagocytic lymphohistiocytosis is a rare secondary disease triggered by viral infections or autoimmune diseases in which elevated activation of the immune response may cause mortal complications. It is reported that the usage of ruxolitinib suppresses cytokine levels and JAK/STAT pathway in Epstein-Barr Virus (EBV) -associated hemophagocytic lymphohistiocytosis [71] .

Anti-viral property of ruxolitinib is associated with Human Immunodeficiency Virus (HIV) and EBV infections which influence primarily immune cells.

inflammation that making conditions more favorable for systemic infection. It is showed that ruxolitinib has toxicity on HIV-1, and HIV-2 infected human peripheral blood mononuclear cells, J o u r n a l P r e -p r o o f inhibits HIV-1 replication in lymphocytes and macrophages and suppresses reactivation of the viruses [72] . It is suggested that these effects of ruxolitinib originate from JAK/STAT pathway inhibition which involved in both viral proliferation and reduction of inflammatory downstream molecules like   IL1β, IL2, IL5, IL6, IL7, IL13, IL15 , and IFNG [73] [74] [75] .

In the same manner, the anti-viral potential of ruxolitinib is also indicated in EBV infection.

Ruxolitinib inhibits EBV-infected PBMC proliferation and reduces elevated inflammatory cytokines by inhibiting activation of especially STAT3 [76, 77] .

Since the JAK/STAT pathway is the primary signal pathway that controls the proliferation of immune cells, suppression of this pathway which causes a reduction in the immune response can also result in the emergence of opportunistic infections.

The development of Polyomavirus (JC-Virus and BK-Virus) related fatal encephalopathy and meningitis has been reported during ruxolitinib treatment [78, 79] . Because the JAK/STAT pathway inhibits Zika Virus (ZIKV) and Hepatitis C Virus (HCV), are members of the Flaviviridae family, it is suggested that ruxolitinib may increase viral replication [80, 81] . It is also reported that Hepadnaviridae family member Hepatitis B Virus (HBV) is reactivated due to ruxolitinib treatment [82] . Infections of different Herpesvirus family members which include Varicella-Zoster Virus (VZV), EBV, and Cytomegalovirus (CMV), have also been reported. Development of gastric ulcer and meningoencephalitis due to EBV and VZV infections has been reported in patients with myelofibrosis and polycythemia vera treated with ruxolitinib, respectively [83, 84] . Ruxolitinib has also been associated with reactivation of CMV, VZV, and EBV during myelofibrosis, graft versus host disease, and myelodysplastic syndrome treatments [85] [86] [87] [88] . Reactivation causes secondary diseases that include lymphoproliferative disorders [89] .

While determining ruxolitinib's potential efficacy against SARS-CoV-2, positive and negative properties in other viral infections constitute an important parameter, but it cannot be expected to be determinant alone.

Since ruxolitinib is a well-tolerated drug and used for the treatment for the elderly population at present, it is suggested as a powerful candidate to overcome the hyperimmune syndrome that raises the mortality numbers in the COVID-19 [68] . There are currently ongoing clinical trials about the potential efficacy of ruxolitinib in COVID-19 related symptoms ( Table 1) .

To determine the potential molecular efficacy of ruxolitinib on genetic alterations determined in various tissues and blood levels of COVID-19 patients, JAK1 and JAK2 by using The STRING Database Version 11. Molecular pathways that include altered genes were determined by the KEGG Pathway Database (Figure 4) . Ruxolitinib reduces the expression of inflammatory biomarkers, particularly cytokine storm syndrome, at both the gene and protein levels in different cells and the blood circulation by inhibiting both JAK1 and JAK2 ( Table 2) .

In this context, it is clear that ruxolitinib, which is used especially in older age patients, has an important potential in overcoming complications that are caused by over activation of the immune system which is triggered through JAK/STAT signaling pathway. Since the JAK/STAT pathway is associated with the regulation of multiple molecular pathways as well as the immune system, inhibition of this pathway will result in many cellular responses via different cross talks. Also, both JAK1 and JAK2 interact directly or indirectly with numerous proteins. When all of the findings are considered, ruxolitinib has an important potential in COVID-19 infection. However, adverse effects such as opportunistic infections that may occur as a result of suppression of the immune system due to JAK/STAT inhibition should also be considered in this process. 

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

None.

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