Abstract
COVID-19 is caused by the Severe Acute Respiratory Syndrome (SARS) coronavirus (Cov)-2, an enveloped virus with a positive-polarity, single-stranded RNA genome. The initial outbreak of the pandemic began in December 2019, and it is affecting the human health of the global community. In common with previous pandemics (Influenza H1N1 and SARS-CoV) and the epidemics of Middle east respiratory syndrome (MERS)-CoV, CoVs target bronchial and alveolar epithelial cells. Virus protein ligands (e.g., haemagglutinin or trimeric spike glycoprotein for Influenza and CoV, respectively) interact with cellular receptors, such as (depending on the virus) either sialic acids, Dipeptidyl peptidase 4 (DPP4), or angiotensin-converting enzyme 2 (ACE2). Host proteases, e.g., cathepsins, furin, or members of the type II transmembrane serine proteases (TTSP) family, such as Transmembrane protease serine 2 (TMPRSS2), are involved in virus entry by proteolytically activating virus ligands. Also involved are Toll Like Receptor (TLR) family members, which upregulate anti-viral and pro-inflammatory mediators [interleukin (IL)-6 and IL-8 and type I and type III Interferons among others], through the activation of Nuclear Factor (NF)-kB. When these events (virus cellular entry and innate immune responses) are uncontrolled, a deleterious systemic response is sometimes encountered in infected patients, leading to the well-described “cytokine storm” and an ensuing multiple organ failure promoted by a downregulation of dendritic cell, macrophage, and T-cell function. We aim to describe how the lung and systemic host innate immune responses affect survival either positively, through downregulating initial viral load, or negatively, by triggering uncontrolled inflammation. An emphasis will be put on host cellular signaling pathways and proteases involved with a view on tackling these therapeutically.
Highlights
COVID-19 is a respiratory disease whose aetiologic agent is a novel beta coronavirus (CoV) called Severe Acute Respiratory Syndrome (SARS)-CoV-2/2019-nCov
The first anatomical/histological reports from the lungs of severely SARS-CoV-2-affected patients experiencing acute respiratory disease syndrome (ARDS) revealed excessive inflammatory activation and destruction of the bronchial and alveolar epithelium, features already observed during the first SARS pandemics in 2003 [3, 4]
It was demonstrated that over-expression of the human Dipeptidyl peptidase 4 (DPP4) in mice promoted Middle east respiratory syndrome (MERS)-CoV infection, causing lethal disease [49], and that Transmembrane protease serine 2 (TMPRSS2) was instrumental in that context [48]
Summary
COVID-19 is a respiratory disease whose aetiologic agent is a novel beta coronavirus (CoV) called Severe Acute Respiratory Syndrome (SARS)-CoV-2/2019-nCov. The first anatomical/histological reports from the lungs of severely SARS-CoV-2-affected patients experiencing acute respiratory disease syndrome (ARDS) revealed excessive inflammatory activation and destruction of the bronchial and alveolar epithelium, features already observed during the first SARS pandemics in 2003 [3, 4] In the latter pandemic, lung alveolar epithelial cells were identified as the most likely site of virus replication, and it was suggested that alveolar macrophages may be responsible for the dissemination of viruses within the lungs [3]. Disease [49], and that TMPRSS2 was instrumental in that context [48]
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