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The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is responsible for the ongoing COVID-19 pandemic, and causes many health complications, including major lung diseases. Besides investigations into the virology of SARS-CoV-2, understanding the immunological routes underlying the clinical manifestations of COVID-19 is important for developing effective therapeutic interventions. The clearance of SARS-CoV-2-infected apoptotic cells by professional efferocytes, through a process termed as 'efferocytosis', is essential for maintaining tissue homeostasis, and reducing the chances of health complications caused by SARS-CoV-2 infection. In this review, we focus on the cellular events leading to engagement of the SARS-CoV-2 with type 2 alveolar cells, and how SARS-COV-2 infection impairs the macrophage anti-inflammatory programming. We also discuss accounts of impaired efferocytosis, and the "cytokine storm" which occur concomitantly with the SARS-CoV-2 infection. Finally, we propose how targeting impaired efferocytosis, due to the SARS-CoV-2 infection, may be a beneficial therapeutic strategy to combat COVID-19, and its complications. [Display omitted] • Efferocytosis, a physiological process essential for maintaining tissue homeostasis, is hampered by SARS-CoV-2 infection. • Engagement with SARS-CoV-2 impairs the efficiency of macrophages, which mediate the phagocytic process. • An imbalance in immune signalling also triggers a 'cytokine storm', which causes tissue inflammation and damage. • Major lung diseases and autoimmune disorders have emerged as common complications in COVID-19 patients. • Boosting efferocytosis, post SARS-CoV-2 infection, could be an effective strategy against COVID-19 and its complications. [ABSTRACT FROM AUTHOR]

• The released HMGB1 and proinflammatory cytokines form A feed-back loop to enhance the inflammatory response due to virus infection. • The inhibition of HMGB1 release or neutralization of extracellular HMGB1 would suppress inflammatory response and disease severity. • Post-translational modifications (PTMs), such as acetylation, are critical for the release of HMGB1 following virus infection. • ROS is potentially involved in the regulation of inflammatory response via interaction with HMGB1. • Intracellular HMGB1 regulates viral replication by interacting with viral genomes, viral proteins, or even cellular proteins. Inflammatory responses, characterized by the overproduction of numerous proinflammatory mediators by immune cells, is essential to protect the host against invading pathogens. Excessive production of proinflammatory cytokines is a key pathogenic factor accounting for severe tissue injury and disease progression during the infection of multiple viruses, which are therefore termed as "cytokine storm". High mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein released either over virus-infected cells or activated immune cells, may act as a proinflammatory cytokine with a robust capacity to potentiate inflammatory response and disease severity. Moreover, HMGB1 is a host factor that potentially participates in the regulation of viral replication cycles with complicated mechanisms. Currently, HMGB1 is regarded as a promising therapeutic target against virus infection. Here, we provide an overview of the updated studies on how HMGB1 is differentially manipulated by distinct viruses to regulate viral diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits an interferon (IFN) deficiency state. • Early treatment with IFN-alpha2 or IFN-beta, preferentially in the early disease stage, may prohibit disease progression. • SARS-CoV-2 may also elicit a cytokine storm, which accounts for disease progression. • JAK1/2 inhibitor treatment with ruxolitinib or baricitinib may decrease mortality by dampening the deadly cytokine storm. • Combination therapy with IFNs and JAK1/2 inhibitor is proposed as a novel and rational treatment modality to be tested in clinical trials. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits an interferon (IFN) deficiency state, which aggravates the type I interferon deficiency and slow IFN responses, which associate with e.g. aging and obesity. Additionally, SARS-CoV-2 may also elicit a cytokine storm, which accounts for disease progression and ultimately the urgent need of ventilator support. Based upon several reports, it has been argued that early treatment with IFN-alpha2 or IFN-beta, preferentially in the early disease stage, may prohibit disease progression. Similarly, preliminary studies have shown that JAK1/2 inhibitor treatment with ruxolitinib or baricitinib may decrease mortality by dampening the deadly cytokine storm, which – in addition to the virus itself - also contributes to multi-organ thrombosis and multi-organ failure. Herein, we describe the rationale for treatment with IFNs (alpha2 or beta) and ruxolitinib emphasizing the urgent need to explore these agents in the treatment of SARS-CoV-2 – both as monotherapies and in combination. In this context, we take advantage of several safety and efficacy studies in patients with the chronic myeloproliferative blood cancers (essential thrombocythemia, polycythemia vera and myelofibrosis) (MPNs), in whom IFN-alpha2 and ruxolitinib have been used successfully for the last 10 (ruxolitinib) to 30 years (IFN) as monotherapies and most recently in combination as well. In the context of these agents being highly immunomodulating (IFN boosting immune cells and JAK1/2 inhibitors being highly immunosuppressive and anti-inflammatory), we also discuss if statins and hydroxyurea, both agents possessing anti-inflammatory, antithrombotic and antiviral potentials, might be inexpensive agents to be repurposed in the treatment of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

• The most important cause of COVID-19 deaths is the development of complications. • Dysregulated immune response and cytokine storm are the most important complications. • The JAK / STAT pathway is the main signal pathway that controls cytokine production. • The JAK1 and JAK2 inhibitor ruxolitinib may be a choice to prevent cytokine storm. • However, the disadvantages of ruxolitinib should also be considered. Ruxolitinib is the first approved JAK1 and JAK2 inhibitor, and is known to interfere with the JAK / STAT signaling pathway, one of the critical cellular signaling pathways involved in the inflammatory response. This review presents an overview of SARS-CoV-2 and the COVID-19 pandemic, and then focuses on the potential efficacy of ruxolitinib in this infection. The potential targets of ruxolitinib were 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 with ruxolitinib or JAK/STAT pathway. [ABSTRACT FROM AUTHOR]

• COVID-19 infection can lead to the development of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome MODS within a few days of disease onset. • A powerful cytokine storm accompanies COVID-19 pneumonia. • The capacity to accurately predict and intervene in the cytokine storm during COVID-19 pneumonia, as well as the ability to design effective specific strategies to block excessive inflammation, is critical for patient survival. Clinical intervention in patients with corona virus disease 2019 (COVID-19) has demonstrated a strong upregulation of cytokine production in patients who are critically ill with SARS-CoV2-induced pneumonia. In a retrospective study of 41 patients with COVID-19, most patients with SARS-CoV-2 infection developed mild symptoms, whereas some patients later developed aggravated disease symptoms, and eventually passed away because of multiple organ dysfunction syndrome (MODS), as a consequence of a severe cytokine storm. Guidelines for the diagnosis and treatment of SARS-CoV-2 infected pneumonia were first published January 30th, 2020; these guidelines recommended for the first time that cytokine monitoring should be applied in severely ill patients to reduce pneumonia related mortality. The cytokine storm observed in COVID-19 illness is also an important component of mortality in other viral diseases, including SARS, MERS and influenza. In view of the severe morbidity and mortality of COVID-19 pneumonia, we review the current understanding of treatment of human coronavirus infections from the perspective of a dysregulated cytokine and immune response. [ABSTRACT FROM AUTHOR]