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.