The COVID-19-, SARS-and MERS-related coronaviruses share many genomic and structural similarities. However, the SARS-CoV-2 is less pathogenic than SARS-CoV and MERS-CoV. Despite some differences in the cytokine patterns, it seems that the cytokine storm plays a crucial role in the pathogenesis of COVID-19-, SARSand MERS. Monocytes and macrophages may be infected by SARS-CoV-2 through ACE2-dependent and ACE2independent pathways. SARS-CoV-2 can effectively suppress the anti-viral IFN response in monocytes and macrophages. Since macrophages and dendritic cells (DCs) act as antigen presenting cells (APCs), the infection of these cells by SARS-CoV-2 impairs the adaptive immune responses against the virus. Upon infection, monocytes migrate to the tissues where they become infected resident macrophages, allowing viruses to spread through all organs and tissues. The SARS-CoV-2-infected monocytes and macrophages can produce large amounts of numerous types of pro-inflammatory cytokines and chemokines, which contribute to local tissue inflammation and a dangerous systemic inflammatory response called cytokine storm. Both local tissue inflammation and the cytokine storm play a fundamental role in the development of COVID-19-related complications, such as acute respiratory distress syndrome (ARDS), which is a main cause of death in COVID-19 patients. Here, we describe the monocytes and macrophage responses during severe coronavirus infections, while highlighting potential therapeutic interventions to attenuate macrophage-related inflammatory reactions in possible approaches for COVID-19 treatment. 1. Introduction The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)mediated COVID-19 has emerged during the late 2019 and caused a serious public health threat, forcing the WHO to announce the SARS-CoV-2 outbreak as a pandemic [1]. SARS-CoV-2, as a member of the coronavirus family, is an enveloped virus containing a positive-sense single-stranded RNA molecule
The lymphopenia as a major immunological abnormality occurs in the majority of severe COVID‐19 patients, which is strongly associated with mortality rate. A low proportion of lymphocytes may express the main receptor for SARS‐CoV‐2, called angiotensin‐converting enzyme 2 (ACE2). Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can also use ACE2‐independent pathways to enter lymphocytes. Both SARS‐CoV‐2‐ and immune‐mediated mechanisms may contribute to the occurrence of lymphopenia through influencing the lymphocyte production, survival or tissue re‐distribution. The metabolic and biochemical changes can also affect the production and survival of lymphocytes in COVID‐19 patients. Lymphopenia can cause general immunosuppression and promote cytokine storm, both of them play an important role in the viral persistence, viral replication, multi‐organ failure and eventually death. Here, a comprehensive view concerning the possible mechanisms that may lead to the lymphocyte reduction in COVID‐19 patients is provided, while highlighting the potential intervention approaches to prevent lymphopenia.
Hyper-inflammatory responses, lymphopenia, unbalanced immune responses, cytokine storm, large viral replication and massive cell death play fundamental roles in the pathogenesis of COVID-19. Extreme production of many kinds of pro-inflammatory cytokines and chemokines occur in severe COVID-19 that called cytokine storm. Signal transducer and activator of transcription-3 (STAT-3) present in the cytoplasm in an inactive form and can be stimulated by a vast range of cytokines, chemokines and growth factors. Thus, STAT-3 can participate in the induction of inflammatory responses during coronavirus infections. STAT-3 can also suppress anti-virus interferon response and induce unbalanced anti-virus adaptive immune response, through influencing Th17-, Th1-, Treg-, and B cell-mediated functions. Furthermore, STAT-3 can contribute to the M2 macrophage polarization, lung fibrosis and thrombosis. Moreover, STAT-3 may be directly targeted by some virus-derived protein and operate as a pro-viral or anti-viral element in a virus-specific process. Here, the possible contribution of STAT-3 to the pathogenesis of COVID-19 was explained, while providing potential approaches to target this transcription factor in an attempt for COVID-19 treatment.
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