Introduction
The emergence in Wuhan China of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered an epidemic of the coronavirus disease 2019 (COVID-19). As of August 3rd2020, the confirmed 18,238,195 cases including 692,872 deaths have been reported worldwide (worldometers.info/coronavirus). At the end of January 2020, the WHO declared COVID-19 a pandemic and a global health emergency.
The family Coronaviridae is subdivided into Torovirinaeand Coronavirinae that contains the generaAlphacoronavirus, Betacoronavirus, Gammacoronavirus, andDeltacoronavirus . The human coronaviruses (HCoV) belong to the αlpha-CoV (HCoV-229E and HCoV-NL63) and beta-CoV (Middle East respiratory syndrome coronavirus -MERS-CoV, SARS-CoV, HCoV-OC43 and HCoV-HKU1) [Table 1;(1–11)]. In comparison with most HCoVs that cause mild upper respiratory tract infections, SARS-CoV, MERS-CoV and SARS-CoV-2 induce severe pneumonia (12). The clinical presentation of COVID-19 ranges from mild ‘flu-like’ symptoms to severe respiratory failure and death although the majority of SARS-CoV-2 infections (80%) are asymptomatic. Common symptoms include fever, cough, fatigue, shortness of breath, headache and pneumonia. In addition, some patients develop gastrointestinal problems (13), neurological manifestations, including headache, dizziness, hyposmia and hypogeusia. Age and comorbidities i.e., hypertension, chronic obstructive pulmonary disease, diabetes, obesity and cardiovascular disease predispose to more severe manifestations including severe respiratory failure, septic shock, coagulation dysfunction, strokes, cardiovascular problems (14) and neurological manifestations (15). Although the origin and transmission of SARS-CoV-2 is unclear genome sequencing reveals marked similarities with SARS-CoV (16). However, in comparison, SARS-CoV-2 spreads more quickly than SARS-CoV, likely due to the 10-20% fold higher in infectivity and transmissibility during the initial non-symptomatic period (4-5 days). In some cases, transmission been reported after development of initial symptoms despite the presence of antibodies (17) indicating that both neutralising antibodies and T cell responses are necessary to prevent reinfection and for protection (18). This is further supported by studies showing PD1+CD57+ T cell exhaustion, depletion or inactivation is associated with viral persistence in severe cases (19).
SARS-CoV-2 is a positive-sense RNA (29,903 nucleotides) enveloped virus of 60 to 140 nm diameter. The envelope is studded with homotrimers spike proteins of 8-12 nm length that are heavily decorated with N-glycans [figure 1]. Similar to other HCoVs, SARS-CoV-2 genome encodes for four structural proteins: the spike (S), membrane (M), envelope (E) and the nucleocapsid (N) protein. The 5’ end of the genome is comprised of ORFa/ab encoding 2 large polyproteins including the replicase protein crucial for self-generation of the non-structural proteins (nsp) while ORFs 2-10 encode the viral structural proteins - spike, envelope, membrane and nucleocapsid, and the accessory proteins [figure 1b]. Differences between the structural, non-structural and accessory proteins of SARS-CoV-2 and other coronaviruses help to explain the high infectivity rate and the range of pathologies observed (16,20). While knowledge of SARS-CoV2 is rapidly emerging parallels with SARS-CoV, as well as ongoing sequencing data and antigenic typing will be crucial to understand the dynamics of the pandemic. SARS-CoV-2 cell entry is similar to SARS-CoV being mediated by the binding of the receptor-binding domain (RBD) of the S1 protein, to the angiotensin-converting enzyme-2 (ACE-2), although other receptors such as CD147 and CD-SIGN have been reported (7,8) [Table 1]. Docking of the RBD to the receptor and the action of furin, a serine protease that separates the S1 and S2 proteins and exposes a second binding domain on S2 that is essential for membrane fusion. Binding of the S protein to ACE-2 requires priming by cell proteases - primarily TMPRSS2, however, TMPRSS2 is expressed by a subset of ACE2+ cells supporting the notion that the virus likely uses other host enzymes such as TMPRSS4, lysosomal cathepsins and neuropilin-1 (21) to augment the impact of furin and expose the RDB thus promoting SARS-CoV-2 entry (3). The structural proteins M, E and N are crucial for stability of the viral genome, viral replication. The nsp and accessory proteins encoded by 10 open reading frames (ORFs) have differing functions during viral replication [Table 2] and many also act to deviate the innate immune repose thus augmenting viral replication and spread. The degree to which the innate immune system is suppressed and evaded clearly determines the viral load and the host’s outcome to infection, the clinical symptoms and the severity of the disease.