Unpuzzling COVID-19: tissue-related signaling pathways associated with SARS-CoV-2 infection and transmission
The new coronavirus disease 19: SARS-CoV-2
Origin, classification, transmission and clinical features
Coronaviruses (CoVs), a family of viruses identified in humans in late 1960s [1,2], are considered relevant pathogens that can infect a broad range of hosts, such as bats, rodents, civets, livestock and arabian camels . In humans, CoV infection may result into mild to severe cases conditions that impact the respiratory, gastrointestinal (GI) and/or central nervous system (CNS) systems [3–5]. Taking into consideration their genomic and phylogenetic features, CoVs are single-stranded positive-sense RNA viruses, largely enveloped in a lipid bilayer, that belong to the Corovaviridae family (Coronavirinae subfamily, Nidovirales order). This virus family consists of four genera (α-, β-, γ- and δ-coronavirus), among of which only α-coronaviruses and β-coronaviruses are capable of infecting mammals [3,5–12].
For the last two centuries, no other severe acute respiratory syndrome (SARS) caused by the other six described human coronaviruses , such as SARS-CoV [6,14] and Middle-East respiratory syndrome coronavirus (MERS-CoV) [7,15], has affected world population in such an unprecedented manner as the most recent β-coronavirus SARS-CoV-2 [9,12,16,17].
First named as 2019 novel coronavirus (2019-nCoV), SARS-CoV-2 was discovered in December 2019 in Wuhan (capital of Hubei Province, China), acting as an unknown pneumonia-causing agent. It has been credited that SARS-CoV-2 originated from zoonotic transfer of bat coronaviruses, possibly through animals in this location [9,12,18–20]. Since then, the coronavirus disease 19 (COVID-19) has rapidly spread across all continents, becoming a public health emergency (pandemic) as announced by World Health Organization (WHO) in early 2020 .
Possible routes of SARS-CoV-2 viral transmission include direct and contact transmissions, such as human to human interaction by droplet inhalation and/or contact with oral/nasal membranes, as well as nosocomial contamination [11,22]. The main COVID-19 symptoms are fever and cough, but other conditions such as anosmia, cardiovascular and GI disorders have been increasingly reported, thus suggesting the presence of multiple targets of infection outside the respiratory tract [9,11,23]. Moreover, COVID-19 has been reported to be particularly more severe in patients with comorbidities unrelated to the respiratory tract, such as hypertension, diabetes and cardiovascular disease [24–27].
Current literature have presented evidence for the potential ability of SARS-CoV-2 to primarily behave as other coronavirus members, such as SARS-CoV and MERS-CoV, to further induce distinct human conditions, but the mechanisms underlying the development of COVID-19 have been poorly elucidated. Therefore, unveiling the signaling pathways elicited (or repressed) upon entry of SARS-CoV-2 into host cells can provide a better knowledge about COVID-19 and also direct to potential pharmacological targets that may counterbalance some of the crucial pathological marks due to this new coronavirus. In this review, we explore the current knowledge of SARS-CoV-2 infection and transmission, focusing on the main aspects of cellular signaling pathways that are impacted by SARS-CoV-2 in targeted organ systems.
Mechanisms of cellular interaction by angiotensin-converting enzyme 2
Similar to other β-coronaviruses, SARS-CoV-2 is mainly composed by four compartments with distinct roles in the viral replication: membrane spike glycoprotein (S), membrane (M), envelope (E) and nucleocapsid (N) . Additionally, SARS-CoV-2 present biological features that resemble other β-coronaviruses class members, especially SARS-CoV, such as genome, protein structure, infection mechanisms [mainly involving the interaction with angiotensin-converting enzyme 2 (ACE2)] and tissue tropism [8,16,20,28,29].
The angiotensin-converting enzyme (ACE) homolog metallopeptidase ACE2 is widely expressed in the human body, including renal, lymphoid and cardiovascular tissues as well as gastroinstestinal (duodenum, jejunum, ileum, cecum and colon), respiratory and central nervous systems . Hamming et al. (2004) have determined the distribution of ACE2 protein by immunohistochemistry, which corroborated previous mRNA expression data. Moreover, relevant immunolabeling identified ACE2 protein in alveolar epithelium cells and capillary endothelium of the lungs, small intestine epithelia, blood vessels and capillaries of the skin, brain endothelium and renal glomerular epithelium . According to studies that elucidated (i) the synthesis of ACE2, (ii) the detection of ACE2 in organs targeted by SARS-CoV-2 and (iii) the mechanisms associating ACE2 with the invasion/replication of coronaviruses, it has demonstrated that ACE2 serves as a functional receptor of SARS-CoV and, particularly, SARS-CoV-2
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