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Interleukin-1- Receptor Kinase 4 Inhibition: Achieving Immunomodulatory Synergy to Mitigate the Impact of COVID-19

, Hyung J. Chun
Published: 23 June 2021

Abstract: COVID-19 is a viral disease caused by a novel coronavirus, SARS-CoV-2, and is responsible for a pandemic since being identified in January 2020, resulting in a severe acute respiratory syndrome (SARS). Although most patients with COVID-19 may experience an asymptomatic, mild, or self-limited illness, many patients rapidly develop dyspnea and pneumonia, requiring hospitalization for pulmonary support. Patients with severe COVID-19 symptoms manifest cytokine release syndrome (CRS), which is associated with systemic inflammation, hemodynamic instability, and multi-organ failure (1). Progression from milder respiratory symptoms to acute respiratory distress syndrome (ARDS) is currently believed to be driven largely due to CRS and be one of main reasons for COVID-19 mortality. The CRS phase of SARS-CoV-2 is thought to occur due to an influx of neutrophils and macrophages as well as elevations of inflammatory cytokines, with higher levels of IL-6, IL-1, IL-8, and IL-18 (1, 2). In CRS, a variety of pro-inflammatory cytokines, including IL-1, IL-6, IL-8, CXCL-10, interferon (INF)-induced chemokines, and tumor necrosis factor (TNF)-α are secreted by alveolar macrophages that drive the inflammatory response and promote further influx of neutrophils, monocytes, and other inflammatory cells (1, 3). During the later stages of COVID-19, there are increases in pro-inflammatory cytokines and low levels of antiviral antibodies and adaptive immune responses noted, similar to previously reported results about SARS-CoV, suggesting innate immunity rather than the adaptive immunity as the driving force for excessive inflammation in COVID-19 associated ARDS (3, 4). In Meizlish et al., proteomic profiling of hospitalized patients with COVID-19 revealed prominent signatures of neutrophil activation in those patients with critical illness (5). Markers of neutrophilic activation, such as granulocyte colony-stimulating factor [G-CSF] and interleukin-8 [IL-8] and neutrophil-derived effectors (resistin [RETN], lipocalin-2 [LCN2]) had the greatest discriminatory power in this study for identifying patients with severe COVID-19 (5). This study represented important findings given that neutrophils are often the first responders in the innate immune response but can have notable collateral damage. Complement activation has also been suggested to play an important role and be a distinct entity in severe COVID-19 infection. In Ma et al., circulating markers of complement activation were found to be higher in patients with respiratory failure in COVID-19 compared to those with non-respiratory failure with COVID-19 and influenza (6). The complement pathway can typically be activated by 3 arms: classical pathway, alternative pathway, and lectin pathway. In this study, increased activation of the alterative pathway was noted and was found to be associated with worse outcomes in COVID-19 infection (6). Studies are currently ongoing to shed more light on the adaptive immunity and antibody response associated with COVID-19. There is data that demonstrates the ability of the SARS-CoV-2 virus to elicit neutralizing antibody response in sera and for those antibodies to be isolated (7, 8). There is evidence that the antibody response is largely mounted against the spike and nucleocapsid proteins of the SARS-CoV-2 virus and the severity of infection is associated with an increase in magnitude and breadth of the humoral response (9). The kinetics of the humoral response equally important, in addition to the magnitude of it, as delayed production of neutralizing antibodies has also been showed to be linked to fatality and impaired viral clearance (10). Activation of human innate immune cells, such as macrophages, through binding of viral antigens from SARS-CoV-2 to cell-surface toll-like receptors (TLRs) has been demonstrated to be a vital mediator of COVID-19 immunopathogenesis (11–13). TLRs are a family of 10 transmembrane receptor proteins (TLR1-TLR10) that recognize pathogen-associated molecular patterns (PAMPs) on viruses, bacteria, and other foreign molecules. TLRs play a major role in the initiation of the innate immune response, with the production of inflammatory cytokines, type I IFN, and other mediators (11–13). The SARS-CoV-2 viral spike protein binds to the extracellular domains of various TLRs, with strongest binding to TLR4. It has been shown that pathogenic human coronaviruses induce oxidized phospholipids that promote acute lung injury by increase lung macrophage cytokine/chemokine production via TLR4 (12). Similarly, SARS-CoV specific GU rich ssRNA fragments induce a high level of TNF- α, IL-6, and IL-12 via TLR7 and TLR8 (14). Collectively, recent in vitro and in vivo experiments suggest that TLRs and innate immunity pro-inflammatory signaling may be important in CRS and major immunopathologic consequences. Immunomodulatory agents, which are commonly used in rheumatologic conditions, have garnered interest for COVID-19 and the hyperinflammatory state. Certain agents are being used to target individual mediators of the inflammatory pathway to mitigate CRS; for example, tocilizumab, which is a monoclonal antibody against the receptor for IL-6, has shown some potential benefit for improving lung function and decreasing length of hospitalization in a large single-center trial (15, 16). Other studies have shown conflicting results with little to no benefit for tocilizumab in mortality of patients with COVID-19 (15, 17–19). In addition, studies have investigated the benefit of steroid use in COVID-19 patients, given their ability for broad-based immunosuppression. In a trial from University of Oxford including 6000 patients with COVID-19 taking 6mg dexamethasone daily, there was lower mortality in ventilated patients and those on oxygen therapy, with on overall decrease in 28-day all cause mortality (15). However, the use of steroids has only been indicated in a subset of COVID-19 patients...
Keywords: COVID-19 / irak4 / immunomodulator / cytokine / Cytokine release syndrome (CRS)

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